Journal of Molecular Biology最新文献

Structured Tandem Repeat Proteins (STRPs) are a subset of repeat proteins characterized by recurring structural motifs, even in cases where sequence similarity between repeats is very low. Despite substantial sequence variability, STRPs preserve conserved secondary-structure elements that underpin a wide range of biological functions. Although millions of protein structures are now publicly available, the accurate detection of STRPs remains challenging. STRPsearch is a recently developed tool for the rapid identification and classification of STRPs. Here, we introduce the STRPsearch web server, an enhanced implementation featuring a user-friendly interface. The server is freely available https://strpsearch.biocomputingup.it/.

The acquisition of vitamin B₁₂ and related cobamides is a key determinant for the fitness of Bacteroidota in the gut. Depending on the species, this uptake process relies on one to four transport systems centered on conserved core outer membrane (OM) complexes composed of the TonB-dependent transporter BtuB and the surface-exposed lipoprotein BtuG. Additionally, the surface-exposed lipoprotein BtuH, although not tightly associated with the BtuBG complex, contributes to cobamide uptake and provides a fitness advantage. Here, we report the functional and structural characterization of BtuJ1 from Bacteroides thetaiotaomicron (B. theta), an additional surface-exposed lipoprotein in B₁₂ uptake loci. BtuJ1 binds vitamin B₁₂ and cobinamide (an intermediate in B₁₂ biosynthesis) with low nM affinity, conferring a fitness advantage in B₁₂-limited environments. Regardless of B₁₂ availability, BtuJ1 is the most abundant of the B₁₂-transport components encoded by B. theta. Under B₁₂-replete conditions, BtuJ1 binds the vitamin, generating a readily available pool for transfer to the core BtuBG transport systems during periods of B₁₂ depletion as demonstrated by in vitro and in vivo B₁₂ transfer experiments. Together, these findings expand the known functionalities of the diverse accessory OM proteins employed by Bacteroidota and underscore the sophisticated strategies these human gut commensals use to secure vitamin B₁₂ in the competitive environment of the human gut.

My independent research, commencing in the late 1980s, was launched with the groundbreaking elucidation of human hepatopoietin-a unique liver-regenerating cytokine bridging signaling and enzymatic function. Building upon this molecular cornerstone, I expanded my focus: shifting from characterizing individual proteins to pioneering the development of a comprehensive proteomics research platform aimed at treating complex human diseases. By the early 2000s, recognizing proteomics' unparalleled capacity to capture the dynamic, spatiotemporal, and functional dimensions of biology, I proposed the visionary 'solar system' framework. This conceptual advance was subsequently adopted in the first Human Proteome Project (HPP) guidelines. Leveraging this momentum, I conceived and led the ambitious Human Liver Proteome Project (HLPP), a landmark initiative that delivered the world's first comprehensive organ proteome atlas and an unprecedented tissue-level protein interaction network. This work revealed fundamental principles governing liver organization, function across space and time, and disease mechanisms. Throughout the 2010s, I led large-scale, disease-centric proteomic profiling to translate molecular insight into clinically actionable disease sub-classifications, robust biomarkers, and novel therapeutic targets. This strategy defined and established Proteomics-Driven Precision Medicine (PDPM)-a transformative paradigm rooted in proteome-level functional insight that began actively reshaping clinical landscapes. To propel the PDPM vision into the big-data era, I organized the establishment of national and international proteomics infrastructures. This effort resulted in the creation of the Proteomic Navigator of the Human Body (π-HuB)-a global initiative poised to integrate multi-modal proteomic intelligence and redefine the future of healthcare for decades to come.

Up-frameshift 1 (UPF1) is best known as a key factor in nonsense-mediated mRNA decay (NMD), a well-conserved surveillance pathway that degrades mRNAs harboring premature termination codons (PTCs). The ATP-dependent RNA helicase UPF1 is recruited to ribosomes terminating at PTCs and triggers mRNA decay. Canonical NMD thereby limits the accumulation of truncated, potentially harmful polypeptides by rapidly eliminating faulty transcripts after the initial rounds of translation. However, emerging evidence from yeast to mammals indicates that UPF1 activity extends beyond simple degradation of PTC-containing mRNAs. Recent work links UPF1 to translating ribosomes, connecting translation dynamics with mRNA surveillance, co-translational quality control of nascent polypeptides, and aggresome targeting of aberrant translation products. These UPF1 functions beyond canonical NMD are increasingly recognized as important for cellular homeostasis. This review focuses on how UPF1 engages ribosomes to influence translation dynamics and coordinates the quality control of mRNA substrates and aberrant translation products. We further discuss the implications of these ribosome-coupled activities for diverse aspects of cellular physiology and disease.