Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

被引：63

作者：

de las Rivas, Matilde ^{[1
]}

Paul Daniel, Earnest James ^{[2
]}

Narimatsu, Yoshiki ^{[3
]}

Companon, Ismael ^{[4
]}

Kato, Kentaro ^{[3
,5
]}

Hermosilla, Pablo ^{[6
]}

Thureau, Aurelien ^{[7
]}

Ceballos-Laita, Laura ^{[1
]}

Coelho, Helena ^{[8
,9
]}

Bernado, Pau ^{[10
]}

Marcelo, Filipa ^{[8
]}

Hansen, Lars ^{[3
]}

Maeda, Ryota ^{[11
]}

Lostao, Anabel ^{[6
,12
,13
]}

Corzana, Francisco ^{[4
]}

Clausen, Henrik ^{[3
]}

Gerken, Thomas A. ^{[2
]}

Hurtado-Guerrero, Ramon ^{[1
,3
,12
]}

机构：

[1] Univ Zaragoza, BIFI, Mariano Esquillor S-N,Campus Rio Ebro, Zaragoza, Spain

[2] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA

[3] Univ Copenhagen, Sch Dent, Dept Cellular & Mol Med, Copenhagen Ctr Glyc, Copenhagen, Denmark

[4] Univ La Rioja, Dept Quim, Ctr Invest Sintesis Quim, Logrono, Spain

[5] Nagasaki Univ, Inst Trop Med, Dept Ecoepidemiol, Nagasaki, Japan

[6] Univ Zaragoza, Inst Nanociencia Aragon, Lab Microscopias Avanzadas, Zaragoza, Spain

[7] Synchrotron SOLEIL, Swing Beamline, Gif Sur Yvette, France

[8] Univ Nova Lisboa, Fac Ciencias & Tecnol, Dept Quim, UCIBIO,REQUIMTE, Caparica, Portugal

[9] Bizkaia Technol Pk, CIC bioGUNE, Derio, Spain

[10] Univ Montpellier, CNRS, Ctr Biochim Struct, INSERM, Montpellier, France

[11] Kyoto Univ, Grad Sch Med, Dept Hematol, Kyoto, Japan

[12] Fdn ARAID, Zaragoza, Spain

[13] Univ Zaragoza, CSIC, Inst Ciencia Mat Aragon, Zaragoza, Spain

来源：

NATURE CHEMICAL BIOLOGY | 2020年 / 16卷 / 03期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; FAMILIAL TUMORAL CALCINOSIS; ALPHA-D-GALACTOSAMINE; SUBSTRATE SPECIFICITIES; LINKED GLYCOSYLATION; CCP4; SUITE; FGF23; MUTATIONS; RECOGNITION; CLONING;

D O I：

10.1038/s41589-019-0444-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif (RHTR)-R-178 down arrow S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3's structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions.

引用

页码：351 / +

页数：14

共 60 条

[41] Mucin-type O-glycosylation is controlled by short- and long-range glycopeptide substrate recognition that varies among members of the polypeptide GalNAc transferase family [J].