Cellular functions and intrinsic attributes of the ATP‐binding Eps15 homology domain‐containing proteins

Abstract

Several cellular processes rely on a cohort of dedicated proteins that manage tubulation, fission, and fusion of membranes. A notably large number of them belong to the dynamin superfamily of proteins. Among them is the evolutionarily conserved group of ATP-binding Eps15-homology domain-containing proteins (EHDs). In the two decades since their discovery, EHDs have been linked to a range of cellular processes that require remodeling or maintenance of specific membrane shapes such as during endocytic recycling, caveolar biogenesis, ciliogenesis, formation of T-tubules in skeletal muscles, and membrane resealing after rupture. Recent work has shed light on their structure and the unique attributes they possess in linking ATP hydrolysis to membrane remodeling. This review summarizes some of these recent developments and reconciles intrinsic protein functions to their cellular roles.

Energy and Dynamics of Caveolae Trafficking

“…In mammals, four EHD orthologs are found (EHD1-4) that show distinct tissue-specific expression, localization, and functions (Pohl et al, 2000 ; George et al, 2007 ). EHD1, 3 and 4 are observed at early and late endosomes and EHD2 is located primarily at the caveolar neck (reviewed in Naslavsky and Caplan, 2011 ; Bhattacharyya and Pucadyil, 2020 ). All EHD proteins are able to bind to and bend phospholipid membranes (Daumke et al, 2007 ; Melo et al, 2017 ; Deo et al, 2018 ).…”

GTP‐stimulated membrane fission by the N‐BAR protein AMPH‐1

“…Prevailing mechanistic models for EHD proteins like RME-1 deviate from the canonical, mechanochemical model for the neuronal dynamin-1. 12,36 Beyond the preference for ATP (not GTP) and very slow hydrolysis rates, EHD proteins (and non-neuronal dynamin-2 37 ;) appear to work with N-BAR protein partners on elongated tubules. 8,14,15,38 As reported previously, 23 we show that the EHD homolog, RME-1, causes membrane tubulation, but does not exhibit membrane fission activity.…”

“…Similarly, previous work indicated that tubules formed with RME-1 and AMPH-1 are significantly shorter than those formed by either protein alone. 8 Although the role for EHD proteins appears disparate, 12,36 there is some evidence linking ATP hydrolysis and membrane fission for the closest RME-1 homolog in humans, EHD-1. 39 Furthermore, rme-1 mutants in C. elegans (and loss of EHD-1 in mammalian cells) block receptor release from enlarged recycling endosomes, suggesting a positive role in carrier formation, and mutations that disrupt the interaction between RME-1 and AMPH-1 are likewise defective in recycling.…”

“…8 The discovery of RME-1, 7,9 a dynamin-like, Eps15 Homology Domain (EHD) ortholog, 10 initially suggested a dynamin-like, mechanochemical mechanism. 11,12 RME-1, the sole EHD protein ortholog in C. elegans, is a nucleoside triphosphate hydrolase 13 that binds and functions with AMPH-1 (the only amphiphysin ortholog in that organism) in a functional partnership that is also observed at the recycling endosome in mammals. 8 In contrast to the dynamin family, studies of EHD proteins from lamprey synapses and mammalian cells suggest that not all EHD proteins induce membrane fission; rather, some stabilize membrane tubules and others inhibit membrane fission, 14,15 leaving the function of RME-1 unresolved.…”

A Review of Mechanics-Based Mesoscopic Membrane Remodelling Methods: Capturing Both the Physics and the Chemical Diversity

“…Besides, due to the presence of long unstructured linkers regions between well-folded domains of scaffold proteins, the effective curvature can be thought to have a distribution rather than a fixed value 135,136 . Scaffold proteins such as Amphiphysin1 from the BAR family 119 , Epsin N-terminal homology domain 137 , dynamic and EHD proteins 47,111,138,139 and AP180 137…”