2m55
From Proteopedia
NMR structure of the complex of an N-terminally acetylated alpha-synuclein peptide with calmodulin
Structural highlights
DiseaseCALM1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. FunctionCALM1_HUMAN Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[1] [2] [3] [4] Publication Abstract from PubMedCalmodulin (CaM) is a calcium binding protein that plays numerous roles in Ca-dependent cellular processes, including uptake and release of neurotransmitters in neurons. alpha-Synuclein (alpha-syn), one of the most abundant proteins in central nervous system neurons, helps maintain presynaptic vesicles containing neurotransmitters and moderates their Ca-dependent release into the synapse. Ca-bound CaM interacts with alpha-syn most strongly at its N-terminus. The N-terminal region of alpha-syn is important for membrane binding, thus CaM could modulate membrane association of alpha-syn in a Ca-dependent manner. In contrast, Ca-free CaM has negligible interaction. The interaction with CaM leads to significant signal broadening in both CaM and alpha-syn NMR spectra, most likely due to conformational exchange. The broadening is much reduced when binding a peptide consisting of the first 19 residues of alpha-syn. In neurons, most alpha-syn is acetylated at the N-terminus, and acetylation leads to a ten-fold increase in binding strength for the alpha-syn peptide (KD = 35 +/- 10 muM). The N-terminally acetylated peptide adopts a helical structure at the N-terminus with the acetyl group contacting the N-terminal domain of CaM, and with less ordered helical structure towards the C-terminus of the peptide contacting the CaM C-terminal domain. Comparison with known structures shows the CaM/alpha-syn complex most closely resembles Ca-bound CaM in a complex with an IQ motif peptide. However, a search comparing the alpha-syn peptide sequence with known CaM targets, including IQ motifs, found no homologies, thus the N-terminal alpha-syn CaM binding site appears to be a novel CaM target sequence. NMR Structure of Calmodulin Complexed to An N-terminally Acetylated alpha-Synuclein Peptide.,Gruschus JM, Yap TL, Pistolesi S, Maltsev AS, Lee JC Biochemistry. 2013 Apr 22. PMID:23607618[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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