6jfm
Mitofusin2 (MFN2)_T111D
Structural highlights
DiseaseMFN2_HUMAN Multiple symmetric lipomatosis;Autosomal dominant Charcot-Marie-Tooth disease type 2A2;Severe early-onset axonal neuropathy due to MFN2 deficiency;Hereditary motor and sensory neuropathy type 5;Hereditary motor and sensory neuropathy type 6. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionMFN2_HUMAN Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion (PubMed:11181170, PubMed:11950885, PubMed:28114303). Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events (PubMed:28114303). Overexpression induces the formation of mitochondrial networks (PubMed:28114303). Membrane clustering requires GTPase activity and may involve a major rearrangement of the coiled coil domains (Probable). Plays a central role in mitochondrial metabolism and may be associated with obesity and/or apoptosis processes (By similarity). Plays an important role in the regulation of vascular smooth muscle cell proliferation (By similarity). Involved in the clearance of damaged mitochondria via selective autophagy (mitophagy) (PubMed:23620051). Is required for PRKN recruitment to dysfunctional mitochondria (PubMed:23620051). Involved in the control of unfolded protein response (UPR) upon ER stress including activation of apoptosis and autophagy during ER stress (By similarity). Acts as an upstream regulator of EIF2AK3 and suppresses EIF2AK3 activation under basal conditions (By similarity).[UniProtKB:Q80U63][UniProtKB:Q8R500][1] [2] [3] [4] [5] Publication Abstract from PubMedMitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease. Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset.,Li YJ, Cao YL, Feng JX, Qi Y, Meng S, Yang JF, Zhong YT, Kang S, Chen X, Lan L, Luo L, Yu B, Chen S, Chan DC, Hu J, Gao S Nat Commun. 2019 Oct 29;10(1):4914. doi: 10.1038/s41467-019-12912-0. PMID:31664033[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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