Structural and Thermodynamic Insights into Chitooligosaccharide Binding to Human Cartilage Chitinase 3-like Protein 2 (CHI3L2 or YKL-39)

Ranok, Araya; Wongsantichon, Jantana; Robinson, Robert; Suginta, Wipa

doi:10.1074/jbc.m114.588905

Cited by 31 publications

(19 citation statements)

References 48 publications

(61 reference statements)

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“…By applying a glycan microarray, performed at the Consortium of Functional Glycomics, the chitooligosaccharides were identified as the best ligands of YKL-39 (17). Structural analysis demonstrates that YKL-39 interacts with chitooligosaccharides through hydrogen bonds and hydrophobic interactions, and compared with other GH-18 members, YKL-39 has the least extended chitin-binding cleft (18). However, the biological relevance of these interactions is questionable, since chitin is not synthesized by mammals, and the tissue expression of YKL-39 rather precludes contact with chitooligosaccharides as a component of the nutrition or pathogens (17).…”

Section: Ym1mentioning

confidence: 99%

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

2020

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YKL-39 belongs to the evolutionarily conserved family of Glyco_18-containing proteins composed of chitinases and chitinase-like proteins. Chitinase-like proteins (CLPs) are secreted lectins that lack hydrolytic activity due to the amino acid substitutions in their catalytic domain and combine the functions of cytokines and growth factors. One of the major cellular sources that produce CLPs in various pathologies, including cancer, are macrophages. Monocytes recruited to the tumor site and programmed by tumor cells differentiate into tumor-associated macrophages (TAMs), which are the primary source of pro-angiogenic factors. Tumor angiogenesis is a crucial process for supplying rapidly growing tumors with essential nutrients and oxygen. We recently determined that YKL-39 is produced by tumor-associated macrophages in breast cancer. YKL-39 acts as a strong chemotactic factor for monocytes and stimulates angiogenesis. Chemotherapy is a common strategy to reduce tumor size and aggressiveness before surgical intervention, but chemoresistance, resulting in the relapse of tumors, is a common clinical problem that is critical for survival in cancer patients. Accumulating evidence indicates that TAMs are essential regulators of chemoresistance. We have recently found that elevated levels of YKL-39 expression are indicative of the efficiency of the metastatic process in patients who undergo neoadjuvant chemotherapy. We suggest YKL-39 as a new target for anti-angiogenic therapy that can be combined with neoadjuvant chemotherapy to reduce chemoresistance and inhibit metastasis in breast cancer patients.

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Section: Ym1mentioning

confidence: 99%

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

2020

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“…Although, later structural analysis appeared inconsistent with a monoglucosamine-binding site [45]. In contrast, YKL-39 binds chito-oligosaccharides, with sugar length determining binding strength [46]. Considering its apparent specialised functions, it is somewhat surprising that further studies have not begun to unlock mechanistic details of YKL-39.…”

Section: Disease Association and Molecular Mechanisms Of Clpsmentioning

confidence: 99%

Chitinase-like proteins as regulators of innate immunity and tissue repair: helpful lessons for asthma?

Sutherland

2018

Biochemical Society Transactions

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Chitinases and chitinase-like proteins (CLPs) belong to the glycoside hydrolase family 18 of proteins. Chitinases are expressed in mammals and lower organisms, facilitate chitin degradation, and hence act as host-defence enzymes. Gene duplication and loss-of-function mutations of enzymatically active chitinases have resulted in the expression of a diverse range of CLPs across different species. CLPs are genes that are increasingly associated with inflammation and tissue remodelling not only in mammals but also across distant species. While the focus has remained on understanding the functions and expression patterns of CLPs during disease in humans, studies in mouse and lower organisms have revealed important and overlapping roles of the CLP family during physiology, host defence and pathology. This review will summarise recent insights into the regulatory functions of CLPs on innate immune pathways and discuss how these effects are not only important for host defence and tissue injury/repair after pathogen invasion, but also how they have extensive implications for pathological processes involved in diseases such as asthma.

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“…All CLPs have specific characteristics in carbohydrate binding site. The binding region is located in (α/β)8 TIM-barrel domain, which allows CLPs to interact with chitin oligosaccharides with high affinity [10,11]. It is crucial to be aware about the binding characteristics of CLP, because it allows prediction of the binding partners and, therefore, prediction of biological functions related to that binding.…”

Section: Common Features Of Clps Familymentioning

confidence: 99%

“…YKL-39 is known to bind to chitooligosaccharides (GlcNac)5 and (GlcNac)6 [11,12], that was demonstrated by glycan array screening, intrinsic tryptophan fluorescence and isothermal titration calorimetry (ITC). There are more binding targets known for YKL-40; it can bind to type I collagen that was revealed by affinity chromatography and surface plasmon resonance [13], to chitooligosaccharides, that shown in protein X-ray crystallography assay [14]; (GlcNac)5 and (GlcNac)4 that revealed by the Western blot [15] and heparin demonstrated by heparin affinity and HPLC chromatography [16].…”

Section: Common Features Of Clps Familymentioning

confidence: 99%

Chitinase-Like Proteins as Promising Markers in Cancer Patients

et al. 2018

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In the present review we collected the main studies regarding the role of chitinase-like proteins (CLPs), belonging to the family of Glyco_18 domain-containing proteins, in different cancers. In humans, 3 chitinaselike proteins have been identified: YKL-40 (CHI3L1), YKL-39 (CHI3L2) and stabilin-1-interacting chitinase-like protein (SI-CLP). CLPs are produced by several types of cells and combine the properties of cytokines and growth factors. The high levels of CLPs were identified in the circulation of the patients with inflammatory diseases and various types of tumors. We highlighted the main known functions of CLPs in normal and pathological conditions, their contribution to metastasis development, angiogenesis, invasion and other processes in cancer, the correlation of the levels of CLPs with tumour progression. Our data also contribute to the understanding of question how CLP could be useful for cancer patient benefit.

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Structural and Thermodynamic Insights into Chitooligosaccharide Binding to Human Cartilage Chitinase 3-like Protein 2 (CHI3L2 or YKL-39)

Cited by 31 publications

References 48 publications

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

Chitinase-like proteins as regulators of innate immunity and tissue repair: helpful lessons for asthma?

Chitinase-Like Proteins as Promising Markers in Cancer Patients

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