Structural Basis of Protein Homeostasis

描述(申请人提供)：细胞蛋白质组的完整性严重依赖于精心设计的蛋白质质量控制机器网络，该网络既帮助新制造的蛋白质折叠，又允许识别和处理末端错误折叠的形式。许多人类疾病，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动态平衡有关。因此，确定蛋白质质量控制机制的作用机制是了解所有活细胞的健康和病理的主要目标。这一机制的一个共同主题是识别部分未折叠的多肽链的能力，以促进它们随后的折叠/重折叠或 或在旨在恢复蛋白质折叠能力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在许多不同的底物上工作，因此在底物结合方面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取得了很大进展，但确定了底物结合结构或定义和验证了底物“识别码”的例子很少。因此，我们缺乏对管理这些蛋白质机器工作的核心原则的理解。我们建议通过专注于一组核心的生理关键系统来弥合这一差距，这些系统覆盖了一系列分子功能，但有一个共同的要求，即必须在分子识别事件中平衡特异性和可塑性。特别是，我们将专注于胞浆伴侣底物的识别(使用HSP70、HSP90和TIRE伴侣家族的例子)和内质网(ER)管腔中未折叠蛋白质的识别，以通过ER相关降解途径(ERAD)降解和通过未折叠蛋白反应(UPR)信号传递。

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).