4h1u | pdb_00004h1u

Nucleotide-free human dynamin-1-like protein GTPase-GED fusion

spinqualitylabelsall models 4h1u, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4h1u is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FLC Related: 4h1v Gene: DNM1L, DLP1, DRP1 (HUMAN) Activity: Dynamin GTPase, with EC number 3.6.5.5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [DNM1L_HUMAN] Note=May be associated with Alzheimer disease through beta-amyloid-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss and neuronal damage. Defects in DNM1L are the cause of encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF) [MIM:614388]. EMPF is a rare autosomal dominant systemic disorder resulting in lack of neurologic development and death in infancy. After birth, infants present in the first week of life with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation. Other features include mildly elevated plasma concentration of very-long-chain fatty acids, lactic acidosis, microcephaly, deep-set eyes, optic atrophy and hypoplasia, and an abnormal gyral pattern in both frontal lobes associated with dysmyelination. Function [DNM1L_HUMAN] Functions in mitochondrial and peroxisomal division. Mediates membrane fission through oligomerization into ring-like structures which wrap around the scission site to constict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism. Required for normal brain development. Facilitates developmentally-regulated apoptosis during neural tube development. Required for a normal rate of cytochrome c release and caspase activation during apoptosis. Also required for mitochondrial fission during mitosis. Required for programmed necrosis execution. May be involved in vesicle transport. Isoform 1 and isoform 4 inhibit peroxisomal division when overexpressed. Publication Abstract from PubMed Human dynamin-1-like protein (DNM1L) is a GTP-driven molecular machine that segregates mitochondria and peroxisomes. To obtain insights into its catalytic mechanism, we determined crystal structures of a construct comprising the GTPase domain and the bundle signaling element (BSE) in the nucleotide-free and GTP-analogue-bound states. The GTPase domain of DNM1L is structurally related to that of dynamin and binds the nucleotide 5'-Guanylyl-imidodiphosphate (GMP-PNP) via five highly conserved motifs, whereas the BSE folds into a pocket at the opposite side. Based on these structures, the GTPase center was systematically mapped by alanine mutagenesis and kinetic measurements. Thus, residues essential for the GTPase reaction were characterized, among them Lys38, Ser39 and Ser40 in the phosphate binding loop, Thr59 from switch I, Asp146 and Gly149 from switch II, Lys216 and Asp218 in the G4 element, as well as Asn246 in the G5 element. Also, mutated Glu81 and Glu82 in the unique 16-residue insertion of DNM1L influence the activity significantly. Mutations of Gln34, Ser35, and Asp190 in the predicted assembly interface interfered with dimerization of the GTPase domain induced by a transition state analogue and led to a loss of the lipid-stimulated GTPase activity. Our data point to related catalytic mechanisms of DNM1L and dynamin involving dimerization of their GTPase domains. Functional Mapping of Human Dynamin-1-Like GTPase Domain Based on X-ray Structure Analyses.,Wenger J, Klinglmayr E, Frohlich C, Eibl C, Gimeno A, Hessenberger M, Puehringer S, Daumke O, Goettig P PLoS One. 2013 Aug 19;8(8):e71835. doi: 10.1371/journal.pone.0071835. PMID:23977156 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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