Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

Abstract

Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis networks mediate MP folding and manage misfolding in the cell. When combined with results from genomic sequencing, these studies have established paradigms for how MP folding and misfolding are linked to the molecular etiologies of a variety of diseases. This emerging framework has paved the way for the development of a new class of small molecule “pharmacological chaperones” that bind to and stabilize misfolded MP variants, some of which are now in clinical use. In this review, we comprehensively outline current perspectives on the folding and misfolding of integral MPs as well as the mechanisms of cellular MP quality control. Based on these perspectives, we highlight new opportunities for innovations that bridge our molecular understanding of the energetics of MP folding with the nuanced complexity of biological systems. Given the many linkages between MP misfolding and human disease, we also examine some of the exciting opportunities to leverage these advances to address emerging challenges in the development of therapeutics and precision medicine.

Computer simulations of protein–membrane systems

“…The interactions would eventually promote release of the peptide from the membrane interior, thereby exposing aggregation-prone hydrophobic regions of the peptide. The results provide mechanistic insights into the GM1-mediated release of membrane inserted Aβ 40 .…”

“…For drug development purposes, there is also continual need to investigate protein-lipid interactions. 40 For atomistic insight into protein-lipid interactions, experimental techniques like X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and cryo-electron microscopy (cryo-EM) are often used. X-ray structures in the 1-3 Å resolution range represent an often dynamic system with single snapshots and the crystallization process sometimes involves harsh treatments capable of generating nonnative protein conformations.…”

“…308 So far, no consensus hypothesis of the molecular cause of AD has emerged, however, due to the presence of Aβ peptide in amyloid plaques, Aβ is widely accepted as a key molecule in AD. Aβ exists in two isoforms, Aβ 40 and Aβ 42 , with the latter being more prone to aggregation and more toxic. 309 Furthermore, several studies have shown that Aβ oligomers and not the fibrils are the causative agent of AD.…”

“…[325][326][327] In vitro studies have shown that DHA inhibits Aβ 42 fibril formation. 328 To better understand the inhibitory role of DHA, Ntarakas et al, 323 carried out MD simulations of Aβ peptide fragments Aβ 1-28 and Aβ [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] in single component bilayers (DMPC-14:0,14:0 or SDPC-18:0,22:6) and in mixed bilayers (DSPE-18:0,18:0, DDPE-22:6,22:6, DPPC-16:0,16:0, DOPC-18:1,18:1) with varying composition. The mixed bilayer is divided into two types based on lipid composition.…”

“…In another related study using PUFAs, Lu et al 324 looked into the role of omega-3 (ω3) and omega-6 (ω6) PUFAs in stabilizing Aβ 29-42 dimer structures by performing extensive AA-MD simulations ($7 μs). The Aβ [29][30][31][32][33][34][35][36][37][38][39][40][41][42] dimers in both helical and β-sheet conformations were fully preinserted into a bilayer of POPC, 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (SAPC ω6 18:0,20:4) and 1-stearoyl-2-docosahexaenoyl-sn-glycero-3phosphocholine (SDPC ω3 18:0,22:6). For the β-sheet conformation, an additional simulation was carried with the peptide fully inserted into a mixed bilayer composed of POPC/SAPC/SDPC lipids.…”