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NMR structure of calmodulin complexed to an N-terminally acetylated α-synuclein peptide.

Gruschus JM, Yap TL, Pistolesi S, Maltsev AS, Lee JC
Biochemistry 52 3436-45 (2013)
Cited: 20 times
EuropePMC logo PMID: 23607618

Abstract

Calmodulin (CaM) is a calcium binding protein that plays numerous roles in Ca-dependent cellular processes, including uptake and release of neurotransmitters in neurons. α-Synuclein (α-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 α-syn most strongly at its N-terminus. The N-terminal region of α-syn is important for membrane binding; thus, CaM could modulate membrane association of α-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 α-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 α-syn. In neurons, most α-syn is acetylated at the N-terminus, and acetylation leads to a 10-fold increase in binding strength for the α-syn peptide (KD = 35 ± 10 μM). 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/α-syn complex most closely resembles Ca-bound CaM in a complex with an IQ motif peptide. However, a search comparing the α-syn peptide sequence with known CaM targets, including IQ motifs, found no homologies; thus, the N-terminal α-syn CaM binding site appears to be a novel CaM target sequence.

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  4. NMR structure of calmodulin complexed to an N-terminally acetylated α-synuclein peptide. Gruschus JM, Yap TL, Pistolesi S, Maltsev AS, Lee JC. Biochemistry 52 3436-3445 (2013)
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  4. Abundant fish protein inhibits α-synuclein amyloid formation. Werner T, Kumar R, Horvath I, Scheers N, Wittung-Stafshede P. Sci Rep 8 5465 (2018)
  5. Did α-Synuclein and Glucocerebrosidase Coevolve? Implications for Parkinson's Disease. Gruschus JM. PLoS One 10 e0133863 (2015)
  6. Confinement Alters the Structure and Function of Calmodulin. Xu G, Cheng K, Wu Q, Liu M, Li C. Angew Chem Int Ed Engl 56 530-534 (2017)
  7. N-Lauroylation during the Expression of Recombinant N-Myristoylated Proteins: Implications and Solutions. Flamm AG, Le Roux AL, Mateos B, Díaz-Lobo M, Storch B, Breuker K, Konrat R, Pons M, Coudevylle N. Chembiochem 17 82-89 (2016)
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