ADAMTS3 explained

A disintegrin and metalloproteinase with thrombospondin motifs 3 is an enzyme that in humans is encoded by the ADAMTS3 gene.^{[1] [2]} The protein encoded by this gene is the major procollagen II N-propeptidase.

Structure

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene is the major procollagen II N-propeptidase.

Function

Because of the high similarity to ADAMTS2, the major substrate of ADAMTS3 had been erroneously assumed to be procollagen II.^[3] However, ADAMTS3 appears largely irrelevant for collagen maturation but instead is required for the activation of the lymphangiogenic growth factor VEGF-C.^[4] Hence, ADAMTS3 is essential for the development and growth of lymphatic vessels. The proteolytic processing of VEGF-C by ADAMTS3 is regulated by the CCBE1 protein.

ADAMTS3 has been shown to cleave reelin, a protein that regulates the proper lamination of the brain cortex and whose signal activity is found to be disrupted in a number of neuropsychiatric conditions.^[5]

Clinical significance

A deficiency of this protein may be responsible for dermatosparaxis, a genetic defect of connective tissues.

Some hereditary forms of lymphedema are caused by mutations in ADAMTS3.^{[6] [7]}

Further reading

• Tang BL . ADAMTS: a novel family of extracellular matrix proteases . The International Journal of Biochemistry & Cell Biology . 33 . 1 . 33–44 . January 2001 . 11167130 . 10.1016/S1357-2725(00)00061-3 .
• Martel-Pelletier J, Welsch DJ, Pelletier JP . Metalloproteases and inhibitors in arthritic diseases . Best Practice & Research. Clinical Rheumatology . 15 . 5 . 805–29 . December 2001 . 11812023 . 10.1053/berh.2001.0195 .
• Hirohata S . [ADAMTS family--new extracellular matrix degrading enzyme] . Seikagaku. The Journal of Japanese Biochemical Society . 73 . 11 . 1333–7 . November 2001 . 11831030 .
• Hurskainen TL, Hirohata S, Seldin MF, Apte SS . ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family . The Journal of Biological Chemistry . 274 . 36 . 25555–63 . September 1999 . 10464288 . 10.1074/jbc.274.36.25555 . free .
• Colige A, Vandenberghe I, Thiry M, Lambert CA, Van Beeumen J, Li SW, Prockop DJ, Lapiere CM, Nusgens BV . Cloning and characterization of ADAMTS-14, a novel ADAMTS displaying high homology with ADAMTS-2 and ADAMTS-3 . The Journal of Biological Chemistry . 277 . 8 . 5756–66 . February 2002 . 11741898 . 10.1074/jbc.M105601200 . free .

External links

• The MEROPS online database for peptidases and their inhibitors: M12.220

Notes and References

1. Tang BL, Hong W . ADAMTS: a novel family of proteases with an ADAM protease domain and thrombospondin 1 repeats . FEBS Letters . 445 . 2–3 . 223–5 . February 1999 . 10094461 . 10.1016/S0014-5793(99)00119-2 . 37955930 .
2. Web site: Entrez Gene: ADAMTS3 ADAM metallopeptidase with thrombospondin type 1 motif, 3.
3. Fernandes RJ, Hirohata S, Engle JM, Colige A, Cohn DH, Eyre DR, Apte SS . Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis . The Journal of Biological Chemistry . 276 . 34 . 31502–9 . August 2001 . 11408482 . 10.1074/jbc.M103466200 . free .
4. Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen VM, Holopainen T, Kivelä R, Ortega S, Kärpanen T, Alitalo K . CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation . Circulation . 129 . 19 . 1962–71 . May 2014 . 24552833 . 10.1161/CIRCULATIONAHA.113.002779 . free .
5. Hattori M, Kohno T . Regulation of Reelin functions by specific proteolytic processing in the brain . Journal of Biochemistry . 169. 5. 511–516. February 2021 . 33566063 . 10.1093/jb/mvab015 . free .
6. Jha SK, Rauniyar K, Karpanen T, Leppänen VM, Brouillard P, Vikkula M, Alitalo K, Jeltsch M . Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1 . Scientific Reports . 7 . 1 . 4916 . July 2017 . 28687807 . 5501841 . 10.1038/s41598-017-04982-1 . 2017NatSR...7.4916J .
7. Brouillard P, Dupont L, Helaers R, Coulie R, Tiller GE, Peeden J, Colige A, Vikkula M . Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3 . Human Molecular Genetics . 26 . 21 . 4095–4104 . November 2017 . 28985353 . 10.1093/hmg/ddx297 . free .