The structural biology of the dynamin‐related proteins: New insights into a diverse, multitalented family

Abstract

Dynamin‐related proteins are multidomain, mechanochemical GTPases that self‐assemble and orchestrate a wide array of cellular processes. Over the past decade, structural insights from X‐ray crystallography and cryo‐electron microscopy have reshaped our mechanistic understanding of these proteins. Here, we provide a historical perspective on these advances that highlights the structural attributes of different dynamin family members and explores how these characteristics affect GTP hydrolysis, conformational coupling and oligomerization. We also discuss a number of lingering challenges remaining in the field that suggest future directions of study.

Structural and functional characterization of the dominant negative P‐loop lysine mutation in the dynamin superfamily protein Vps1

“…The minimal DSP GTPase‐BSE fusion construct has previously been used for structural and functional characterization of several DSPs . The dynamin‐1 or the Vps1 GTPase‐BSE constructs homodimerize in the presence of the transition state mimic GDP.AlFx but remain monomeric in the absence of nucleotide, or in the presence of GDP or the non‐hydrolyzable GTP analogs GMPPCP or GTPγS .…”

“…We also note that in the Vps1 GTPase‐BSE GMPPCP‐bound structure, the conformation of D214 in the dimer partner, which typically reaches across the interface to contact Q52, is well ordered in each of the monomers in the asymmetric unit. D214 is part of the trans ‐ stabilizing loop . In dynamin‐1, mutation of the D214 equivalent (D180) blocks assembly‐stimulated GTPase activity, for which dimerization is required.…”

“…The dynamin‐superfamily proteins (DSPs) are a family of large GTPases that self‐assemble into helices, have low affinities for guanine nucleotides and function as mechanochemical enzymes that catalyze critical trafficking, membrane remodeling, and antiviral activities in cells . To varying extents, members of the family share domain organizations which invariably include a large GTPase domain, a bundle signaling element (BSE) or closely‐related module that acts in intramolecular signaling, and a Stalk that is responsible for self‐assembly.…”

“…To varying extents, members of the family share domain organizations which invariably include a large GTPase domain, a bundle signaling element (BSE) or closely‐related module that acts in intramolecular signaling, and a Stalk that is responsible for self‐assembly. Additional modules that may be found serve to fine‐tune the molecular properties of the DSP and may aid in recruitment, membrane tethering, or scission …”

Overview: Traffic at atomic resolution

“…Two reviews highlight advances in understanding familiar coat proteins: Audhya co‐workers describe new regulatory factors in COPII trafficking, while Hollopeter and co‐workers highlight advances in understanding conformational regulatory changes by the AP1 and AP2 clathrin adaptors. Advances in single particle cryo‐EM enable mechanistic insights into dynamin‐related proteins from Ford and Chappie and into tethers from Ungermann and Kümmel . Cryo‐electron tomography reconstructions provide an exciting first view of an assembled retromer coat in vitro in an overview from the study by Collins et al Finally, Schwappach and co‐workers couple phylogenetics with structural predictions to uncover a requirement for chaperone proteins in biogenesis of tail‐anchored proteins across all domains of life.…”