Cryo-EM structure of human mitochondrial HSPD1

David P Klebl,Matthew C Feasey,Emma L Hesketh,Neil A Ranson,Heiko Wurdak,Frank Sobott,Robin S Bon,Stephen P Muench

doi:10.1016/j.isci.2020.102022

David P Klebl, Matthew C Feasey + Show 6 more

Open Access

https://doi.org/10.1016/j.isci.2020.102022

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Journal: iScience	Publication Date: Dec 31, 2020
Citations: 18	License type: cc-by

Affiliation: University of Leeds, University of Antwerp

Abstract

SummaryChaperonins play an important role in folding newly synthesized or translocated proteins in all organisms. The bacterial chaperonin GroEL has served as a model system for the understanding of these proteins. In comparison, its human homolog, known as mitochondrial heat shock protein family member D1 (HSPD1) is poorly understood. Here, we present the structure of HSPD1 in the apo state determined by cryo-electron microscopy (cryo-EM). Unlike GroEL, HSPD1 forms mostly single ring assemblies in the absence of co-chaperonin (HSPE1). Comparison with GroEL shows a rotation and increased flexibility of the apical domain. Together with published structures of the HSPD1/HSPE1 co-chaperonin complex, this work gives insight into the structural changes that occur during the catalytic cycle. This new understanding of HSPD1 structure and its rearrangements upon complex formation may provide new insights for the development of HSPD1-targeting treatments against a diverse range of diseases including glioblastoma.

Highlights

Chaperonins are molecular chaperones forming ring-shaped complexes that catalyze protein folding through the capture of unfolded polypeptides and confinement within a central cavity driven by ATP hydrolysis (Horwich et al, 2007)
The bacterial chaperonin GroEL has served as a model system for the understanding of these proteins
We present the structure of heat shock protein family member D1 (HSPD1) in the apo state determined by cryo-electron microscopy

Summary

Introduction

Chaperonins are molecular chaperones forming ring-shaped complexes that catalyze protein folding through the capture of unfolded polypeptides and confinement within a central cavity driven by ATP hydrolysis (Horwich et al, 2007). ATP and GroES binding between the two rings is coupled by negative cooperativity, whereas ATP binding within one ring is positively cooperative (Saibil et al, 2013; Dyachenko et al, 2013). This cooperativity is thought to be important for function: a mutant GroEL, forming single rings and lacking the negative inter-ring cooperativity, gives rise to deadend complexes (Weissman et al, 1995)

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