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Neoplasia. 2018 Feb;20(2):182-192. doi: 10.1016/j.neo.2017.11.011. Epub 2017 Dec 20.

A Heparin Binding Motif Rich in Arginine and Lysine is the Functional Domain of YKL-40.

Author information

1
Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqi Road, Shanghai, China 200092; Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand 12120.
2
Department of Biology, Morrill Science Center South, University of Massachusetts, Amherst, USA 01003.
3
Department of Surgery, Baystate Medical Center, School of Medicine, University of Massachusetts, USA 01199.
4
The Key laboratory of Shanghai and Department of General Surgery, Shanghai Jiao Tong University, School of Medicine, 1665 Kongjiang Road, Shanghai, China 200092.
5
Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqi Road, Shanghai, China 200092.
6
Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqi Road, Shanghai, China 200092; Department of Biology, Morrill Science Center South, University of Massachusetts, Amherst, USA 01003; The Key laboratory of Shanghai and Department of General Surgery, Shanghai Jiao Tong University, School of Medicine, 1665 Kongjiang Road, Shanghai, China 200092. Electronic address: rongshao@sjtu.edu.cn.

Abstract

The heparin-binding glycoprotein YKL-40 (CHI3L1) is intimately associated with microvascularization in multiple human diseases including cancer and inflammation. However, the heparin-binding domain(s) pertinent to the angiogenic activity have yet been identified. YKL-40 harbors a consensus heparin-binding motif that consists of positively charged arginine (R) and lysine (K) (RRDK; residues 144-147); but they don't bind to heparin. Intriguingly, we identified a separate KR-rich domain (residues 334-345) that does display strong heparin binding affinity. A short synthetic peptide spanning this KR-rich domain successfully competed with YKL-40 and blocked its ability to bind heparin. Three individual point mutations, where alanine (A) substituted for K or R (K337A, K342A, R344A), led to remarkable decreases in heparin-binding ability and angiogenic activity. In addition, a neutralizing anti-YKL-40 antibody that targets these residues and prevents heparin binding impeded angiogenesis in vitro. MDA-MB-231 breast cancer cells engineered to express ectopic K337A, K342A or R344A mutants displayed reduced tumor development and compromised tumor vessel formation in mice relative to control cells expressing wild-type YKL-40. These data reveal that the KR-rich heparin-binding motif is the functional heparin-binding domain of YKL-40. Our findings shed light on novel molecular mechanisms underlying endothelial cell angiogenesis promoted by YKL-40 in a variety of diseases.

PMID:
29274508
PMCID:
PMC5773473
DOI:
10.1016/j.neo.2017.11.011
[Indexed for MEDLINE]
Free PMC Article

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