7lu8 | pdb_00007lu8
Structure of the cryptic HMA domain of the human copper transporter ATP7A
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. Publication Abstract from PubMedATP7A and ATP7B are structurally similar but functionally distinct active copper transporters that regulate copper levels in the human cells and deliver copper to the biosynthetic pathways. Both proteins have a chain of six cytosolic metal-binding domains (MBDs) believed to be involved in the copper-dependent regulation of the activity and intracellular localization of these enzymes. Although all the MBDs are quite similar in structure, their spacing differs markedly between ATP7A and ATP7B. We show by NMR that the long polypeptide between MBD1 and MBD2 of ATP7A forms an additional seventh metastable domain, which we called HMA1A (heavy metal associated domain 1A). The structure of HMA1A resembles the MBDs but contains no copper-binding site. The HMA1A domain, which is unique to ATP7A, may modulate regulatory interactions between MBD1-3, contributing to the distinct functional properties of ATP7A and ATP7B. At sixes and sevens: cryptic domain in the metal binding chain of the human copper transporter ATP7A.,Uhlemann EE, Lee W, Tonelli M, Dmitriev OY Biophys J. 2021 Aug 28. pii: S0006-3495(21)00695-0. doi:, 10.1016/j.bpj.2021.08.029. PMID:34461106[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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