2M55: NMR Structure of the Complex of an N-terminally Acetylated Alpha- Synuclein Peptide With Calmodulin

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 10-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 toward the C-terminus of the peptide contacting the CaM C-terminal domain. Comparison with known structures shows that 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.
PDB ID: 2M55Download
MMDB ID: 109782
PDB Deposition Date: 2013/2/13
Updated in MMDB: 2013/12 
Experimental Method:
solution nmr
Source Organism:
Similar Structures:
Biological Unit for 2M55: dimeric; determined by author
Molecular Components in 2M55
Label Count Molecule
Proteins (2 molecules)
Molecule annotation
Alpha-synuclein(Gene symbol: SNCA)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

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