Pub Date : 2024-07-01Epub Date: 2024-07-02DOI: 10.1146/annurev-clinpsy-080822-045011
Noelle M Hurd
Racism and other forms of oppression threaten the well-being of racially and ethnically marginalized youth. Models of risk and resilience for marginalized youth have stressed the importance of addressing contextual and structural risk while emphasizing promotive factors such as cultural capital within their communities. Increasingly, research has focused on collective antiracist action as a form of coping with structural oppression. Importantly, supportive intergenerational relationships that develop within youths' everyday contexts may play a key role in catalyzing and reinforcing youths' engagement in antiracist action. This review advances a novel model for understanding how supportive nonparental adults from youths' everyday lives (i.e., natural mentors) influence youths' positive developmental outcomes and participation in antiracist action and how collective antiracist action, in turn, fosters liberation and racial justice. The creation of a more just and equitable society contributes to positive development among racially and ethnically marginalized youth.
{"title":"Promoting Positive Development Among Racially and Ethnically Marginalized Youth: Advancing a Novel Model of Natural Mentoring.","authors":"Noelle M Hurd","doi":"10.1146/annurev-clinpsy-080822-045011","DOIUrl":"10.1146/annurev-clinpsy-080822-045011","url":null,"abstract":"<p><p>Racism and other forms of oppression threaten the well-being of racially and ethnically marginalized youth. Models of risk and resilience for marginalized youth have stressed the importance of addressing contextual and structural risk while emphasizing promotive factors such as cultural capital within their communities. Increasingly, research has focused on collective antiracist action as a form of coping with structural oppression. Importantly, supportive intergenerational relationships that develop within youths' everyday contexts may play a key role in catalyzing and reinforcing youths' engagement in antiracist action. This review advances a novel model for understanding how supportive nonparental adults from youths' everyday lives (i.e., natural mentors) influence youths' positive developmental outcomes and participation in antiracist action and how collective antiracist action, in turn, fosters liberation and racial justice. The creation of a more just and equitable society contributes to positive development among racially and ethnically marginalized youth.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-07-02DOI: 10.1146/annurev-clinpsy-080822-042337
Michael S Businelle, Olga Perski, Emily T Hébert, Darla E Kendzor
Substance use disorders (SUDs) have an enormous negative impact on individuals, families, and society as a whole. Most individuals with SUDs do not receive treatment because of the limited availability of treatment providers, costs, inflexible work schedules, required treatment-related time commitments, and other hurdles. A paradigm shift in the provision of SUD treatments is currently underway. Indeed, with rapid technological advances, novel mobile health (mHealth) interventions can now be downloaded and accessed by those that need them anytime and anywhere. Nevertheless, the development and evaluation process for mHealth interventions for SUDs is still in its infancy. This review provides a critical appraisal of the significant literature in the field of mHealth interventions for SUDs with a particular emphasis on interventions for understudied and underserved populations. We also discuss the mHealth intervention development process, intervention optimization, and important remaining questions.
{"title":"Mobile Health Interventions for Substance Use Disorders.","authors":"Michael S Businelle, Olga Perski, Emily T Hébert, Darla E Kendzor","doi":"10.1146/annurev-clinpsy-080822-042337","DOIUrl":"10.1146/annurev-clinpsy-080822-042337","url":null,"abstract":"<p><p>Substance use disorders (SUDs) have an enormous negative impact on individuals, families, and society as a whole. Most individuals with SUDs do not receive treatment because of the limited availability of treatment providers, costs, inflexible work schedules, required treatment-related time commitments, and other hurdles. A paradigm shift in the provision of SUD treatments is currently underway. Indeed, with rapid technological advances, novel mobile health (mHealth) interventions can now be downloaded and accessed by those that need them anytime and anywhere. Nevertheless, the development and evaluation process for mHealth interventions for SUDs is still in its infancy. This review provides a critical appraisal of the significant literature in the field of mHealth interventions for SUDs with a particular emphasis on interventions for understudied and underserved populations. We also discuss the mHealth intervention development process, intervention optimization, and important remaining questions.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-07-02DOI: 10.1146/annurev-clinpsy-080822-051727
Roderick J Little
Methods for handling missing data in clinical psychology studies are reviewed. Missing data are defined, and a taxonomy of main approaches to analysis is presented, including complete-case and available-case analysis, weighting, maximum likelihood, Bayes, single and multiple imputation, and augmented inverse probability weighting. Missingness mechanisms, which play a key role in the performance of alternative methods, are defined. Approaches to robust inference, and to inference when the mechanism is potentially missing not at random, are discussed.
{"title":"Missing Data Analysis.","authors":"Roderick J Little","doi":"10.1146/annurev-clinpsy-080822-051727","DOIUrl":"10.1146/annurev-clinpsy-080822-051727","url":null,"abstract":"<p><p>Methods for handling missing data in clinical psychology studies are reviewed. Missing data are defined, and a taxonomy of main approaches to analysis is presented, including complete-case and available-case analysis, weighting, maximum likelihood, Bayes, single and multiple imputation, and augmented inverse probability weighting. Missingness mechanisms, which play a key role in the performance of alternative methods, are defined. Approaches to robust inference, and to inference when the mechanism is potentially missing not at random, are discussed.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-07-02DOI: 10.1146/annurev-clinpsy-081122-010256
Jillian K Peterson, James A Densley, Molly Hauf, Jack Moldenhauer
This in-depth review delves into the multifaceted realm of mass shootings and explores their epidemiology from a psychological perspective. The article presents a comprehensive examination of the prevalence, perpetrator and victim profiles, motives, and contributing factors associated with mass shootings. By investigating the intricate relationship between masculinity, domestic violence, military service, social media, fame-seeking, suicidal ideation, mental illness, and firearms, this article sheds light on the multifaceted nature of mass shootings. Moreover, it discusses the importance of implementing effective prevention strategies to address this growing public health concern. The findings from this review serve as a valuable resource for researchers, practitioners, policy makers, and the community at large, facilitating a deeper understanding of mass shootings and fostering the development of evidence-based solutions to prevent these tragic incidents.
{"title":"Epidemiology of Mass Shootings in the United States.","authors":"Jillian K Peterson, James A Densley, Molly Hauf, Jack Moldenhauer","doi":"10.1146/annurev-clinpsy-081122-010256","DOIUrl":"10.1146/annurev-clinpsy-081122-010256","url":null,"abstract":"<p><p>This in-depth review delves into the multifaceted realm of mass shootings and explores their epidemiology from a psychological perspective. The article presents a comprehensive examination of the prevalence, perpetrator and victim profiles, motives, and contributing factors associated with mass shootings. By investigating the intricate relationship between masculinity, domestic violence, military service, social media, fame-seeking, suicidal ideation, mental illness, and firearms, this article sheds light on the multifaceted nature of mass shootings. Moreover, it discusses the importance of implementing effective prevention strategies to address this growing public health concern. The findings from this review serve as a valuable resource for researchers, practitioners, policy makers, and the community at large, facilitating a deeper understanding of mass shootings and fostering the development of evidence-based solutions to prevent these tragic incidents.</p>","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1146/annurev-biochem-030122-044347
Noortje de Haan, Mathias I. Nielsen, Hans H. Wandall
The complex carbohydrate structures decorating human proteins and lipids, also called glycans, are abundantly present at cell surfaces and in the secretome. Glycosylation is vital for biological processes including cell–cell recognition, immune responses, and signaling pathways. Therefore, the structural and functional characterization of the human glycome is gaining more and more interest in basic biochemistry research and in the context of developing new therapies, diagnostic tools, and biotechnology applications. For glycomics to reach its full potential in these fields, it is critical to appreciate the specific factors defining the function of the human glycome. Here, we review the glycosyltransferases (the writers) that form the glycome and the glycan-binding proteins (the readers) with an essential role in decoding glycan functions. While abundantly present throughout different cells and tissues, the function of specific glycosylation features is highly dependent on their context. In this review, we highlight the relevance of studying the glycome in the context of specific carrier proteins, cell types, and subcellular locations. With this, we hope to contribute to a richer understanding of the glycome and a more systematic approach to identifying the roles of glycosylation in human physiology.
{"title":"Reading and Writing the Human Glycocode","authors":"Noortje de Haan, Mathias I. Nielsen, Hans H. Wandall","doi":"10.1146/annurev-biochem-030122-044347","DOIUrl":"https://doi.org/10.1146/annurev-biochem-030122-044347","url":null,"abstract":"The complex carbohydrate structures decorating human proteins and lipids, also called glycans, are abundantly present at cell surfaces and in the secretome. Glycosylation is vital for biological processes including cell–cell recognition, immune responses, and signaling pathways. Therefore, the structural and functional characterization of the human glycome is gaining more and more interest in basic biochemistry research and in the context of developing new therapies, diagnostic tools, and biotechnology applications. For glycomics to reach its full potential in these fields, it is critical to appreciate the specific factors defining the function of the human glycome. Here, we review the glycosyltransferases (the writers) that form the glycome and the glycan-binding proteins (the readers) with an essential role in decoding glycan functions. While abundantly present throughout different cells and tissues, the function of specific glycosylation features is highly dependent on their context. In this review, we highlight the relevance of studying the glycome in the context of specific carrier proteins, cell types, and subcellular locations. With this, we hope to contribute to a richer understanding of the glycome and a more systematic approach to identifying the roles of glycosylation in human physiology.","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":16.6,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140806292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1146/annurev-biochem-080923-043654
Alexander M Soohoo, D. Cogan, Krystal L Brodsky, C. Khosla
Three decades of studies on the multifunctional 6-deoxyerythronolide B synthase have laid a foundation for understanding the chemistry and evolution of polyketide antibiotic biosynthesis by a large family of versatile enzymatic assembly lines. Recent progress in applying chemical and structural biology tools to this prototypical assembly-line polyketide synthase (PKS) and related systems has highlighted several features of their catalytic cycles and associated protein dynamics. There is compelling evidence that multiple mechanisms have evolved in this enzyme family to channel growing polyketide chains along uniquely defined sequences of 10-100 active sites, each of which is used only once in the overall catalytic cycle of an assembly-line PKS. Looking forward, one anticipates major advances in our understanding of the mechanisms by which the free energy of a repetitive Claisen-like reaction is harnessed to guide the growing polyketide chain along the assembly line in a manner that is kinetically robust yet evolutionarily adaptable.
三十年来对多功能 6-脱氧赤藓醇内酯 B 合成酶的研究,为了解多酮内酯抗生素生物合成的化学和进化奠定了基础。最近,在将化学和结构生物学工具应用于这种原型装配线聚酮内酯合成酶(PKS)和相关系统方面取得了进展,突显了其催化循环和相关蛋白质动态的一些特征。有令人信服的证据表明,在这个酶家族中已经演化出多种机制,可以沿着由 10-100 个活性位点组成的独特定义序列引导生长的多酮苷链,而每个活性位点在组装线式多酮苷合成酶的整个催化循环中只使用一次。展望未来,我们对重复性克来森类反应自由能的利用机制的理解有望取得重大进展,从而引导不断生长的多酮苷链沿着装配线以一种动力学上稳健、进化上适应性强的方式前进。
{"title":"Structure and Mechanisms of Assembly-Line Polyketide Synthases.","authors":"Alexander M Soohoo, D. Cogan, Krystal L Brodsky, C. Khosla","doi":"10.1146/annurev-biochem-080923-043654","DOIUrl":"https://doi.org/10.1146/annurev-biochem-080923-043654","url":null,"abstract":"Three decades of studies on the multifunctional 6-deoxyerythronolide B synthase have laid a foundation for understanding the chemistry and evolution of polyketide antibiotic biosynthesis by a large family of versatile enzymatic assembly lines. Recent progress in applying chemical and structural biology tools to this prototypical assembly-line polyketide synthase (PKS) and related systems has highlighted several features of their catalytic cycles and associated protein dynamics. There is compelling evidence that multiple mechanisms have evolved in this enzyme family to channel growing polyketide chains along uniquely defined sequences of 10-100 active sites, each of which is used only once in the overall catalytic cycle of an assembly-line PKS. Looking forward, one anticipates major advances in our understanding of the mechanisms by which the free energy of a repetitive Claisen-like reaction is harnessed to guide the growing polyketide chain along the assembly line in a manner that is kinetically robust yet evolutionarily adaptable.","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":16.6,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140657016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.1146/annurev-biochem-062917-012322
Amanda L. Peiffer, A.E. Dugan, L.L. Kiessling
Human lectins are integral to maintaining microbial homeostasis on the skin, in the blood, and at mucosal barriers. These proteins can recognize microbial glycans and inform the host about its microbial status. In accordance with their roles, their production can vary with tissue type. They also can have unique structural and biochemical properties, and they can influence microbial colonization at sites proximal and distal to their tissue of origin. In line with their classification as innate immune proteins, soluble lectins have long been studied in the context of acute infectious disease, but only recently have we begun to appreciate their roles in maintaining commensal microbial communities (i.e., the human microbiota). This review provides an overview of soluble lectins that operate at host–microbe interfaces, their glycan recognition properties, and their roles in physiological and pathological mechanisms.
{"title":"Soluble Human Lectins at the Host–Microbe Interface","authors":"Amanda L. Peiffer, A.E. Dugan, L.L. Kiessling","doi":"10.1146/annurev-biochem-062917-012322","DOIUrl":"https://doi.org/10.1146/annurev-biochem-062917-012322","url":null,"abstract":"Human lectins are integral to maintaining microbial homeostasis on the skin, in the blood, and at mucosal barriers. These proteins can recognize microbial glycans and inform the host about its microbial status. In accordance with their roles, their production can vary with tissue type. They also can have unique structural and biochemical properties, and they can influence microbial colonization at sites proximal and distal to their tissue of origin. In line with their classification as innate immune proteins, soluble lectins have long been studied in the context of acute infectious disease, but only recently have we begun to appreciate their roles in maintaining commensal microbial communities (i.e., the human microbiota). This review provides an overview of soluble lectins that operate at host–microbe interfaces, their glycan recognition properties, and their roles in physiological and pathological mechanisms.","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":16.6,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140626315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.1146/annurev-biochem-032620-104731
Carolina Cano-Prieto, Agustina Undabarrena, Ana Calheiros de Carvalho, Jay D Keasling, Pablo Cruz-Morales
Natural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification, biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.
{"title":"Triumphs and Challenges of Natural Product Discovery in the Postgenomic Era.","authors":"Carolina Cano-Prieto, Agustina Undabarrena, Ana Calheiros de Carvalho, Jay D Keasling, Pablo Cruz-Morales","doi":"10.1146/annurev-biochem-032620-104731","DOIUrl":"https://doi.org/10.1146/annurev-biochem-032620-104731","url":null,"abstract":"Natural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification, biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":16.6,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140683589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-15DOI: 10.1146/annurev-biochem-030222-111227
Harald W. Platta, Julia Jeske, Nadine Schmidt, Ralf Erdmann
Peroxisomes are organelles that play a central role in lipid metabolism and cellular redox homeostasis. The import of peroxisomal matrix proteins by peroxisomal targeting signal (PTS) receptors is an ATP-dependent mechanism. However, the energy-dependent steps do not occur early during the binding of the receptor–cargo complex to the membrane but late, because they are linked to the peroxisomal export complex for the release of the unloaded receptor. The first ATP-demanding step is the cysteine-dependent monoubiquitination of the PTS receptors, which is required for recognition by the AAA+ peroxins. They execute the second ATP-dependent step by extracting the ubiqitinated PTS receptors from the membrane for release back to the cytosol. After deubiquitination, the PTS receptors regain import competence and can facilitate further rounds of cargo import. Here, we give a general overview and discuss recent data regarding the ATP-dependent steps in peroxisome protein import.
过氧物酶体是一种细胞器,在脂质代谢和细胞氧化还原平衡中发挥着核心作用。过氧化物酶体靶向信号(PTS)受体导入过氧化物酶体基质蛋白是一种 ATP 依赖性机制。然而,能量依赖性步骤不是在受体-货物复合体与膜结合的早期发生,而是在后期发生,因为它们与过氧化物酶体导出复合体相关联,以释放卸载的受体。第一个需要 ATP 的步骤是 PTS 受体的半胱氨酸依赖性单泛素化,这是 AAA+ 过氧化物酶识别所必需的。它们执行的第二个 ATP 依赖性步骤是将泛素化的 PTS 受体从膜中提取出来,释放回细胞质。去泛素化后,PTS 受体恢复了导入能力,并能促进下一轮的货物导入。在此,我们将对过氧化物酶体蛋白质导入过程中的 ATP 依赖性步骤进行概述并讨论最新数据。
{"title":"ATP-Dependent Steps in Peroxisomal Protein Import","authors":"Harald W. Platta, Julia Jeske, Nadine Schmidt, Ralf Erdmann","doi":"10.1146/annurev-biochem-030222-111227","DOIUrl":"https://doi.org/10.1146/annurev-biochem-030222-111227","url":null,"abstract":"Peroxisomes are organelles that play a central role in lipid metabolism and cellular redox homeostasis. The import of peroxisomal matrix proteins by peroxisomal targeting signal (PTS) receptors is an ATP-dependent mechanism. However, the energy-dependent steps do not occur early during the binding of the receptor–cargo complex to the membrane but late, because they are linked to the peroxisomal export complex for the release of the unloaded receptor. The first ATP-demanding step is the cysteine-dependent monoubiquitination of the PTS receptors, which is required for recognition by the AAA+ peroxins. They execute the second ATP-dependent step by extracting the ubiqitinated PTS receptors from the membrane for release back to the cytosol. After deubiquitination, the PTS receptors regain import competence and can facilitate further rounds of cargo import. Here, we give a general overview and discuss recent data regarding the ATP-dependent steps in peroxisome protein import.","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":16.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-15DOI: 10.1146/annurev-biochem-030122-051144
Dario R. Alessi, Suzanne R. Pfeffer
Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.
{"title":"Leucine-Rich Repeat Kinases","authors":"Dario R. Alessi, Suzanne R. Pfeffer","doi":"10.1146/annurev-biochem-030122-051144","DOIUrl":"https://doi.org/10.1146/annurev-biochem-030122-051144","url":null,"abstract":"Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.","PeriodicalId":7980,"journal":{"name":"Annual review of biochemistry","volume":null,"pages":null},"PeriodicalIF":16.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140599062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}