Molecular Basis of Ca(II)-Induced Tetramerization and Transition-Metal Sequestration in Human Calprotectin.
Molecular Basis of Ca(II)-Induced Tetramerization and Transition-Metal Sequestration in Human Calprotectin.
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DOI：
10.1021/jacs.1c06402
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发表时间：
2021-11-03
影响因子：
15
通讯作者：
Nolan EM
中科院分区：
文献类型：
--
作者：
Silvers R;Stephan JR;Griffin RG;Nolan EM
Human calprotectin (CP, S100A8/S100A9 oligomer, MRP8/MRP14 oligomer) is an abundant innate immune protein that contributes to the host metal-withholding response. Its ability to sequester transition metal nutrients from microbial pathogens depends on a complex interplay of Ca(II) binding and self-association, which converts the αβ heterodimeric apo protein into a Ca(II)-bound (αβ)2 heterotetramer that displays enhanced transition metal affinities, antimicrobial activity, and protease stability. A paucity of structural data on the αβ heterodimer has hampered molecular understanding of how Ca(II) binding enables CP to exert its metal-sequestering innate immune function. We report solution NMR data that reveal how Ca(II) binding affects the structure and dynamics of the CP αβ heterodimer. These studies provide a structural model in which the apo αβ heterodimer undergoes conformational exchange and switches between two states, a tetramerization-incompetent or “inactive” state and a tetramerization-competent or “active” state. Ca(II) binding to the EF-hands of the αβ heterodimer causes the active state to predominate, resulting in self-association and formation of the (αβ)2 heterotetramer. Moreover, Ca(II) binding causes local and allosteric ordering of the His3Asp and His6 metal-binding sites, respectively. Ca(II) binding to the non-canonical EF-hand of S100A9 positions (A9)D30 and organizes the His3Asp site. Remarkably, Ca(II) binding causes allosteric effects in the C-terminal region of helix αIV of S100A9, which stabilizes the α-helicity at positions H91 and H95 and thereby organizes the functionally versatile His6 site. Collectively, this study illuminates the molecular basis for how CP responds to high extracellular Ca(II) concentrations, which enables its metal-sequestering host-defense function.
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影响因子：
15
作者：
Brophy MB;Nakashige TG;Gaillard A;Nolan EM
通讯作者：
Nolan EM
影响因子：
15
作者：
Adhikari, Jagat;Stephan, Jules R.;Gross, Michael L.
通讯作者：
Gross, Michael L.
影响因子：
14.9
作者：
Burley SK;Bhikadiya C;Bi C;Bittrich S;Chen L;Crichlow GV;Christie CH;Dalenberg K;Di Costanzo L;Duarte JM;Dutta S;Feng Z;Ganesan S;Goodsell DS;Ghosh S;Green RK;Guranović V;Guzenko D;Hudson BP;Lawson CL;Liang Y;Lowe R;Namkoong H;Peisach E;Persikova I;Randle C;Rose A;Rose Y;Sali A;Segura J;Sekharan M;Shao C;Tao YP;Voigt M;Westbrook JD;Young JY;Zardecki C;Zhuravleva M
通讯作者：
Zhuravleva M
影响因子：
2.9
作者：
FARROW, NA;MUHANDIRAM, R;KAY, LE
通讯作者：
KAY, LE
影响因子：
56.9
作者：
Corbin, Brian D.;Seeley, Erin H.;Skaar, Eric P.
通讯作者：
Skaar, Eric P.