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Structure. 2018 Aug 7;26(8):1080-1090.e5. doi: 10.1016/j.str.2018.05.010. Epub 2018 Jun 21.

Magnesium Activates Microsecond Dynamics to Regulate Integrin-Collagen Recognition.

Author information

1
Department of Chemistry & Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, USA; Center for Integrative Proteomics Research, Rutgers University, 174 Frelinghuysen Road, Piscataway, NJ 08854, USA.
2
Department of Chemistry & Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, USA.
3
Department of Chemistry & Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, USA; Center for Integrative Proteomics Research, Rutgers University, 174 Frelinghuysen Road, Piscataway, NJ 08854, USA. Electronic address: jean.baum@rutgers.edu.

Abstract

Integrin receptors bind collagen via metal-mediated interactions that are modulated by magnesium (Mg2+) levels in the extracellular matrix. Nuclear magnetic resonance-based relaxation experiments, isothermal titration calorimetry, and adhesion assays reveal that Mg2+ functions as both a structural anchor and dynamic switch of the α1β1 integrin I domain (α1I). Specifically, Mg2+ binding activates micro- to millisecond timescale motions of residues distal to the binding site, particularly those surrounding the salt bridge at helix 7 and near the metal ion-dependent adhesion site. Mutagenesis of these residues impacts α1I functional activity, thereby suggesting that Mg-bound α1I dynamics are important for collagen binding and consequent allosteric rearrangement of the low-affinity closed to high-affinity open conformation. We propose a multistep recognition mechanism for α1I-Mg-collagen interactions involving both conformational selection and induced-fit processes. Our findings unravel the multifaceted role of Mg2+ in integrin-collagen recognition and assist in elucidating the molecular mechanisms by which metals regulate protein-protein interactions.

KEYWORDS:

CPMG relaxation dispersion; NMR spectroscopy; ZZ exchange; collagen interactions; conformational selection; dynamics; induced fit; integrin α(1) I domain; magnesium regulation; metal binding

PMID:
29937357
PMCID:
PMC6615728
DOI:
10.1016/j.str.2018.05.010
[Indexed for MEDLINE]
Free PMC Article

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