Sora Valentina, Kumar Mukesh, Maiani Emiliano, Lambrughi Matteo, Tiberti Matteo, Papaleo Elena
Computational Biology Laboratory, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark.
Translational Disease System Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Front Cell Dev Biol. 2020 Jun 10;8:420. doi: 10.3389/fcell.2020.00420. eCollection 2020.
Autophagy is a conserved and essential intracellular mechanism for the removal of damaged components. Since autophagy deregulation is linked to different kinds of pathologies, it is fundamental to gain knowledge on the fine molecular and structural details related to the core proteins of the autophagy machinery. Among these, the family of human ATG8 proteins plays a central role in recruiting other proteins to the different membrane structures involved in the autophagic pathway. Several experimental structures are available for the members of the ATG8 family alone or in complex with their different biological partners, including disordered regions of proteins containing a short linear motif called LC3 interacting motif. Recently, the first structural details of the interaction of ATG8 proteins with biological membranes came into light. The availability of structural data for human ATG8 proteins has been paving the way for studies on their structure-function-dynamic relationship using biomolecular simulations. Experimental and computational structural biology can help to address several outstanding questions on the mechanism of human ATG8 proteins, including their specificity toward different interactors, their association with membranes, the heterogeneity of their conformational ensemble, and their regulation by post-translational modifications. We here summarize the main results collected so far and discuss the future perspectives within the field and the knowledge gaps. Our review can serve as a roadmap for future structural and dynamics studies of the ATG8 family members in health and disease.
自噬是一种保守且必不可少的细胞内机制，用于清除受损成分。由于自噬失调与多种病理状况相关，因此了解与自噬机制核心蛋白相关的精细分子和结构细节至关重要。其中，人类ATG8蛋白家族在将其他蛋白招募到自噬途径中涉及的不同膜结构上发挥着核心作用。单独的ATG8家族成员或与它们不同生物伴侣（包括含有称为LC3相互作用基序的短线性基序的蛋白质无序区域）形成的复合物，都有几个实验结构。最近，ATG8蛋白与生物膜相互作用的首个结构细节得以揭示。人类ATG8蛋白结构数据的可用性为使用生物分子模拟研究它们的结构-功能-动力学关系铺平了道路。实验和计算结构生物学有助于解决关于人类ATG8蛋白机制的几个突出问题，包括它们对不同相互作用分子的特异性、它们与膜的结合、它们构象集合的异质性以及它们的翻译后修饰调控。我们在此总结了迄今为止收集的主要结果，并讨论了该领域的未来前景和知识空白。我们的综述可作为未来对健康和疾病中ATG8家族成员进行结构和动力学研究的路线图。
