Structural Basis of Protein Homeostasis

描述（由申请人提供）：细胞蛋白质组的完整性关键取决于蛋白质质量控制机器的复杂网络，该网络既有助于新制备蛋白质的折叠，又允许识别和处理末端错误折叠形式。许多不同的人类疾病，包括家族性蛋白质折叠疾病、神经退行性疾病、糖尿病和癌症，以及正常衰老都与未能维持适当的蛋白质稳态有关。因此，定义蛋白质质量控制机制的作用机制是寻求理解所有活细胞中的健康和病理学的主要目标。这种机制的一个共同主题是识别未折叠多肽链的部分的能力，以促进其随后的折叠/重折叠，或 降解，或在旨在恢复蛋白质折叠能力的供需平衡的适应性反应中发出信号。蛋白质质量控制中的大多数分子事件作用于许多不同的底物，因此在底物结合中具有相当大的可塑性。虽然在这些机器的各个部件的结构和功能分析方面已经取得了很大进展，但很少有确定衬底结合结构或定义和验证衬底“识别代码”的例子。因此，我们缺乏对这些蛋白质机器运作的核心原理的理解。我们建议弥合这一差距，专注于一套核心的生理关键系统，涵盖了一系列的分子特征，但共享的共同要求，必须平衡特异性和可塑性的分子识别事件。特别是，我们将专注于胞质伴侣底物识别（使用伴侣的hsp 70，hsp 90和TRIC家族的例子）和识别内质网（ER）内腔中的未折叠蛋白，通过ER相关降解途径（ERAD）降解和通过未折叠蛋白反应（UPR）进行信号传导。

DESCRIPTION (provided by applicant): The integrity of the cellular proteome is critically dependent on an elaborate network of protein quality control machines that both aid in the folding of newly made proteins and allow for the recognition and disposal of terminally misfolded forms. Many diverse human diseases, including familial protein folding diseases, neurodegenerative diseases, diabetes, and cancer, as well as normal aging have been linked to the failure to maintain proper protein homeostasis. Thus defining the mechanism of action of the protein quality control machinery is a major goal in the quest for understanding of health and pathology in all living cells. A common theme to this machinery is the ability to recognize portions of unfolded polypeptide chains, either to facilitate their subsequent folding/refolding or degradation, or to signal in adaptive responses aimed at restoring the balance between supply and demand of the protein folding capacity. Most molecular events in protein quality control work on many diverse substrates and hence possess considerable plasticity in substrate binding. While much progress has been made in structural and functional analysis of individual components of these machines, there are few examples where substrate-bound structures have been determined or where a substrate "recognition code" has been defined and validated. As such, we are lacking in our understanding of core principles that govern workings of these protein machines. We propose to bridge this gap by focusing on a core set of physiologically critical systems that cover a range of molecular features but share the common requirement of having to balance specificity and plasticity in molecular recognition events. In particular, we wil focus on cytosolic chaperone substrate recognition (using examples of the hsp70, hsp90, and TRIC families of chaperones) and the recognition of unfolded proteins in the lumen of the endoplasmic reticulum (ER) for degradation via the ER-associated degradation pathway (ERAD) and for signaling via the unfolded protein response (UPR).