ATTRv-V30M amyloid fibrils from heart and nerves exhibit structural homogeneity

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-10-17 DOI:10.1016/j.str.2024.09.021

Binh An Nguyen, Shumaila Afrin, Anna Yakubovska, Virender Singh, Rose Pedretti, Parker Bassett, Maja Pekala, Jaime Vaquer Alicea, Peter Kunach, Lanie Wang, Andrew Lemoff, Barbara Kluve-Beckerman, Lorena Saelices

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Abstract

Amyloidogenic transthyretin (ATTR) amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin. Transthyretin is primarily produced in tetrameric form by the liver, but also by retinal epithelium and choroid plexus. The deposition of these fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryoelectron microscopy (cryo-EM), we investigated fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found consistent fibril structures from both tissues, similar to cardiac fibrils previously described, but different from vitreous humor fibrils of the same genotype. Our findings, along with previous ATTR fibrils structural studies, suggest a uniform fibrillar architecture across different tissues when transthyretin originates from the liver. This study advances our understanding of how deposition and production sites influence fibril structure in ATTRv-V30M amyloidosis.

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来自心脏和神经的 ATTRv-V30M 淀粉样蛋白纤维在结构上具有同质性

淀粉样变性转甲状腺素（ATTR）淀粉样变性病是一种以转甲状腺素淀粉样纤维沉积为特征的全身性疾病。转甲状腺素主要由肝脏以四聚体形式产生，视网膜上皮和脉络丛也会产生。这些纤维沉积在心肌和周围神经中，分别导致心肌病和神经病。我们使用冷冻电子显微镜（cryo-EM）研究了从一名 ATTRv-V30M 患者的心脏和神经组织中提取的纤维。我们从这两种组织中发现了一致的纤维结构，与之前描述的心脏纤维相似，但与同一基因型的玻璃体纤维不同。我们的发现以及之前的 ATTR 纤维结构研究表明，当转甲状腺素来源于肝脏时，不同组织的纤维结构是一致的。这项研究加深了我们对 ATTRv-V30M 淀粉样变性中沉积和生成部位如何影响纤维结构的理解。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.