2kmv
From Proteopedia
Solution structure of the nucleotide binding domain of the human Menkes protein in the ATP-free form
Structural highlights
DiseaseATP7A_HUMAN Defects in ATP7A are the cause of Menkes disease (MNKD) [MIM:309400; also known as kinky hair disease. MNKD is an X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency. MNKD results in progressive neurodegeneration and connective-tissue disturbances: focal cerebral and cerebellar degeneration, early growth retardation, peculiar hair, hypopigmentation, cutis laxa, vascular complications and death in early childhood. The clinical features result from the dysfunction of several copper-dependent enzymes.[1] [2] [3] [4] [5] [6] [7] [8] [9] Defects in ATP7A are the cause of occipital horn syndrome (OHS) [MIM:304150; also known as X-linked cutis laxa. OHS is an X-linked recessive disorder of copper metabolism. Common features are unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary defects. The skeletal abnormalities included occipital horns, short, broad clavicles, deformed radii, ulnae and humeri, narrowing of the rib cage, undercalcified long bones with thin cortical walls and coxa valga.[10] [11] Defects in ATP7A are a cause of distal spinal muscular atrophy X-linked type 3 (DSMAX3) [MIM:300489. DSMAX3 is a neuromuscular disorder. Distal spinal muscular atrophy, also known as distal hereditary motor neuronopathy, represents a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.[12] FunctionATP7A_HUMAN May supply copper to copper-requiring proteins within the secretory pathway, when localized in the trans-Golgi network. Under conditions of elevated extracellular copper, it relocalized to the plasma membrane where it functions in the efflux of copper from cells. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedWe report the solution NMR structures of the N-domain of the Menkes protein (ATP7A) in the ATP-free and ATP-bound forms. The structures consist of a twisted antiparallel six-stranded beta-sheet flanked by two pairs of alpha-helices. A protein loop of 50 amino acids located between beta 3 and beta 4 is disordered and mobile on the subnanosecond time scale. ATP binds with an affinity constant of (1.2 +/- 0.1) x 10(4) m(-1) and exchanges with a rate of the order of 1 x 10(3) s(-1). The ATP-binding cavity is considerably affected by the presence of the ligand, resulting in a more compact conformation in the ATP-bound than in the ATP-free form. This structural variation is due to the movement of the alpha1-alpha2 and beta2-beta 3 loops, both of which are highly conserved in copper(I)-transporting P(IB)-type ATPases. The present structure reveals a characteristic binding mode of ATP within the protein scaffold of the copper(I)-transporting P(IB)-type ATPases with respect to the other P-type ATPases. In particular, the binding cavity contains mainly hydrophobic aliphatic residues, which are involved in van der Waal's interactions with the adenine ring of ATP, and a Glu side chain, which forms a crucial hydrogen bond to the amino group of ATP. The binding mode of ATP revealed by the solution structure of the N-domain of human ATP7A.,Banci L, Bertini I, Cantini F, Inagaki S, Migliardi M, Rosato A J Biol Chem. 2010 Jan 22;285(4):2537-44. Epub 2009 Nov 16. PMID:19917612[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Banci L | Bertini I | Cantini F | Inagaki S | Migliardi M | Rosato A
