Dynamin-2 function and dysfunction along the secretory pathway

Abstract

Dynamin-2 is a ubiquitously expressed mechano-GTPase involved in different stages of the secretory pathway. Its most well-known function relates to the scission of nascent vesicles from the plasma membrane during endocytosis; however, it also participates in the formation of new vesicles from the Golgi network, vesicle trafficking, fusion processes and in the regulation of microtubule, and actin cytoskeleton dynamics. Over the last 8 years, more than 20 mutations in the dynamin-2 gene have been associated to two hereditary neuromuscular disorders: Charcot-Marie-Tooth neuropathy and centronuclear myopathy. Most of these mutations are grouped in the pleckstrin homology domain; however, there are no common mutations associated with both disorders, suggesting that they differently impact on dynamin-2 function in diverse tissues. In this review, we discuss the impact of these disease-related mutations on dynamin-2 function during vesicle trafficking and endocytotic processes.

Keywords: Charcot–Marie–Tooth neuropathy; actin; centronuclear myopathy; dynamin-2; endocytosis; exocytosis; microtubules; mutations.

Figure 1

Diagram of dynamin structure and localization of dynamin-2 mutations linked to CNM and CMT. Dynamins are multimodular proteins comprising five highly conserved structural domains: a large N-terminal GTPase domain (G-domain), a middle domain, a PH domain that bind phosphoinositides, a GTPase effector domain (GED), and a C-terminal proline rich domain (PRD) that interacts with SH3-domain containing proteins. Most common disease-related dynamin-2 mutations are represented. Note that almost all dynamin-2 mutations identified in CNM and CMT patients are clustered into the PH domains; only one CNM-linked mutation has been found in GED, and one related to CMT has been identified in the PRD. The D555del3 mutation is one of the products of a 9-bp deletion in the exon 14 (1652_1659 + 1delATGAGGAGg) of the dynamin-2 gene (9). This gene deletion also results in a 65-kDa truncated protein (9). For that reason here is described as D555del3, K554fs. An updated database of DNM2 mutations is at the website www.umd.be/DNM2/ (10).