YKL 40

is a non-enzymatic chitinase-like protein. It is able to bind chitin but does not possess the enzymatic activity needed to cleave chitinase. YKL-40 is the human form of chitinase-3 -like protein 1 also referred to as CHI3L1. It is referred to as YKL because of the three amino acid residues (Y, K, and L) present at the N terminus. The 40 comes from the weight of the protein which is around 40kDa. Previous crystallizations have shown a YKL-40 three-dimensional structure that consists of a (β/α)8- barrel domain. It also has a secondary domain comprised of six antiparallel β-strands with one α-helix (α + β) domain after β7. Full-length genomic chains can be observed in UniProt. The complete structure and 3D analysis can be found in the OCA atlas. For a complete guided tour, FirstGlance is recommended.

Function

YKL-40 serves several biological functions. It catalyzes cell proliferation and growth. If YKL-40 is silenced, the proliferation of HEK293 and U87 decreases. Inversely, The expression of YKL-40 promotes the growth of fetal lung fibroblasts, epithelial cells, and chondrocytes found in the joints. It is able to promote this cell growth through Akt signaling and phosphorylation of . It also can increase smooth muscle cell proliferation and growth in humans with asthma. YKL-40 works hand in hand with and promotes the growth of fibroblasts that are integral in tissue fibrosis. During tissue repair, YKL-40 is able to manage where smooth muscle cell is placed and where it sticks. YKL-40 also can protect cells from cell death. It is able to prevent cell apoptosis triggered by inflammatory reactions in the body. It is able to do this through PKB and AKT activation through phosphorylation, as well as inhibition of Fas expression, and Faim induction. One of the most important roles YKL-40 play is in the immune system. It is used to differentiate and activate immune cells. They primarily control the differentiation of Th1 and Th2 using activated T cells. If CD4T+ cells do not have YKL-40, they differentiate into Th1 cells. This has a major impact on cytotoxic T lymphocyte expression which is important to increase anti-tumor immunity. YKL- 40 is expressed more when Th2 inflammatory responses are stimulated. YKL-40 also functions in regulating the formation and break down of the extracellular matrix. “The extracellular matrix helps cells to bind together and regulates a number of cellular functions, such as adhesion, migration, proliferation, and differentiation.” The extracellular matrix is the first barrier that invasive tumor cells face when invading a cell. YKL-40 obstructs this by stopping the breakdown of collagen and hyaluronic acid which make up a bulk of the extracellular matrix. It also suppresses the E-cadherin complex which functions to form adherin junctions between cells. When E-cadherin is suppressed, signals that promote tumor cell invasion are intensified. If the E-cadherin complex is suppressed, the enzymatic activity of metalloproteinase 9 (MMP-9) is enhanced, promoting tumor cell invasion through the degradation of the extracellular matrix. It also facilitates the secretions of MMP-1, MMP-3, MMP-13. These play a direct role in degrading cartilage and directly affect the progression of osteoarthritis. MMP-1, MMP-3, MMP-13, and MMP-9 can be viewed on FirstGlance.

Evolutionary Significance

YKL-40 belongs to the glycoside hydrolase family 18. The specific gene is found on chromosome 1q31-1q32. It is around 8 kilobase-pairs of genomic DNA. Originally, it was found in human articular chondrocytes in the cartilage. Later, it was found in a culture supernatant of MG63 cells.

Interacting Receptors and Ligands

Binding Complex

YKL-40 forms interactions with IL-13Ra2 and IL-13 and makes a multimeric complex. The 3D structure of this can be found here. The multimeric complex interacts with IGFBP-3R, an insulin-like growth factor. The binding of IGFBP-3R activates the Wnt/β-catenin, Erk, and Akt pathways. This regulates cell signaling pathways that control biological functions such as Inflammatory responses and apoptosis Gal-3 can interact with the multimeric complex and actively competes with IGFBP-3R for binding. The binding of Gal-3 increases the apoptotic character of YKL-40. For a complete guided tour, the use of FirstGlance is recommended.

Chitin

Chitin is a derivative of glucose that is found in many classes of prokaryotes and cell walls of algae, plants, and fungi. YKL-40 lacks enzymatic activity because of a single amino acid substitution in the chitinase 3 like catalytic domain. In this, the glutamic acid residue is switched to a leucine. Because of the residue change, YKL-40 binds to chitin quite strongly. Longer chitin monosaccharides bind to central groove areas, while disaccharides bind to sites further away. The complete structure and 3D analysis of Chitin can be found in the OCA atlas. A complete 3D guided tour can be found on FirstGlance.

Hyaluronic Acid

Hyaluronic acid makes up a significant portion of the extracellular matrix of connective, and neural tissue. Hyaluronic acid is a negatively charged, non-sulfated glycosaminoglycan. As such, it is highly linked to YKL-40 production. Amino acid sequencing of YKL-40 indicates two potential binding motifs of YKL-40 for Hyaluronic acid located at residues 147-155 and 369-377. Hyaluronic acid is actively considered as a biomarker for inflammatory diseases in conjunction with YKL-40. The complete structure and 3D analysis of hyaluronic acid can be found in the OCA atlas. A complete 3D guided tour can be found on FirstGlance.

Heparin

Heparin is a sulfur-rich glycosaminoglycan, widely used as an anticoagulant that prevents the formation of blood clots in the human body. YKL-40 contains a heparin-binding motif consisting of arginine(R) and lysine(K) on the main YKL-40 domain. Further X-ray crystallography shows that instead of binding on that heparin-binding motif, heparin binds to another binding site located at the C-terminus of the protein. This binding site is a KR-rich domain. YKL-40 can bind to a heparin sulfate chain of Syn-1. YKL-40 then serves as a bridge for coordination between Syn-1 and integrin αvβ3. As a result, the MAPK, Erk, and PI3K pathways are stimulated. Through the same mechanism, YKL-40 can serve as a connection between Syn-1 and integrin αvβ5, thus activating the FAK signaling pathway as well as triggering upregulation of vascular endothelial growth factor or VEGF. The complete structure and 3D analysis of heparin can be found in the OCA atlas. A complete 3D guided tour can be found on FirstGlance. Crystallography information can be accessed at PDBe.

Disease

Cardiovascular Disease

High YKL-40 levels have been correlated with two times the risk of a venous thromboembolic stroke. Higher YKL-40 levels are also indicative of hypertension and pulmonary atrial hypertension. Most significantly, plasma levels of YKL-40 are found in the epicardial adipose tissue which is the visceral fat surrounding the cardiac muscles. It is thought that plasma YKL-40 levels are highly indicative of cardiovascular disease because YKL-40 silencing may inhibit the progression of cardiac plaque and positive inflammatory interventions. Overall, higher expression of YKL-40 in humans indicates the long-term mortality of patients with cardiovascular disease.

Respiratory Disease

YKL-40 directly correlates to higher levels of expression of MUC5AC. This controls mucus production in the respiratory tract and lead to sputum production and chronic cough which are symptoms of chronic inflammatory airway disease. YKL-40 also inhibits caspase-1-dependent macrophage proptosis. This enhances the tolerance of antibacterial responses in the lung. This is achieved by inhibiting inflammasome activation and the production of type 1, 2, and 17 cytokines. In normally functioning airways without the presence of YKL-40, Type 1 cytokines had an improved inflammatory response. In the same conditions, without YKL-40, type 2 and type 17 cytokines were induced. This contributed to fibrotic airway reconstruction. The promoter on a single nucleotide polymorphism of YKL-40 is linked to asthma and chronic bronchial strain. There is an upregulation of YKL-40 in subjects suffering from chronic obstructive pulmonary disease.

Oncological Disease

There is a high positive correlation between the high expression of YKL-40 and the presence of several carcinomas. This includes ovarian, kidney, colon, lung, prostate, sarcoma, and glioblastoma. The high expression of YKL-40 is linked to high carcinoma-linked mortality rates. YKL-40 facilitates the rapid growth of SW480 cells by the phosphorylation of Erk and MAPK pathways. Subjects with carcinoma metastasis also exhibit high levels of plasma YKL-40. Functionally, the degradation of the extracellular matrix encourages cancer cell migration, promoting metastasis. The triggered inflammatory response by YKL-40 is also a landmark of cancer metastasis. In vitro studies have found that YKL-40 promotes the secretion of TNF and IL-8 in SW480 cells. This in turn activates the Nk KB signaling complex and increases cancer cell invasion. Inhibition of YKL-40 increases Th1 cytokine production and cytotoxic T lymphocyte reactions. This increases tumor immunity and can decrease metastasis.

Neurological Disease

In neurodegenerative conditions such as Alzheimer’s and Parkinson’s, YKL-40 can serve as a biomarker. It is highly disease-specific. Neuroinflammation has been linked as a contributor to different forms of dementia. Particularly in Alzheimer’s disease, elevated YKL-40 levels were seen in clusters around β-amyloid plaques. The distribution of YKL-40 is even between the white and gray matter of the brain. Interestingly, YKL-40 levels are not elevated in dementia with Lewy bodies. YKL-40 is currently being investigated as a blood-based biomarker for the diagnosis of clinical neurodegenerative disease.