View source for 2m55


==NMR structure of the complex of an N-terminally acetylated alpha-synuclein peptide with calmodulin==
<StructureSection load='2m55' size='340' side='right'caption='[[2m55]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2m55]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2M55 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2M55 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALM1, CALM, CAM, CAM1, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2m55 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m55 OCA], [https://pdbe.org/2m55 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2m55 RCSB], [https://www.ebi.ac.uk/pdbsum/2m55 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2m55 ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/SYUA_HUMAN SYUA_HUMAN]] Note=Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1.  Defects in SNCA are the cause of Parkinson disease type 1 (PARK1) [MIM:[https://omim.org/entry/168601 168601]]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.<ref>PMID:9197268</ref> <ref>PMID:9462735</ref> <ref>PMID:14755719</ref>   Defects in SNCA are the cause of Parkinson disease type 4 (PARK4) [MIM:[https://omim.org/entry/605543 605543]]. A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.  Defects in SNCA are the cause of dementia Lewy body (DLB) [MIM:[https://omim.org/entry/127750 127750]]. A neurodegenerative disorder clinically characterized by mental impairment leading to dementia, parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease. 
== Function ==
[[https://www.uniprot.org/uniprot/SYUA_HUMAN SYUA_HUMAN]] May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Calmodulin (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<ref>PMID:23607618</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2m55" style="background-color:#fffaf0;"></div>

==See Also==
*[[Alpha-synuclein|Alpha-synuclein]]
*[[Calmodulin 3D structures|Calmodulin 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Gruschus, J M]]
[[Category: Lee, J C]]
[[Category: Maltsev, A S]]
[[Category: Pistolesi, S]]
[[Category: Yap, T]]
[[Category: Ca-binding]]
[[Category: Calcium binding protein-protein fibril complex]]
[[Category: Protein/peptide]]