3nzi

Structural highlights

Disease

[HTRA1_HUMAN] Variations in the promoter region of HTRA1 are the cause of susceptibility to age-related macular degeneration type 7 (ARMD7) [MIM:610149]. ARMD is the leading cause of vision loss and blindness among older individuals in the developed word. It is classified as either dry (nonneovascular) or wet (neovascular). ARMD7 is a wet form, in which new blood vessels form and break beneath the retina. This leakage causes permanent damage to surrounding retinal tissue, distorting and destroying central vision. Wet ARMD is more prevalent among Asians than Caucasians.^{[1] [2]} Defects in HTRA1 are the cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) [MIM:600142]. CARASIL is characterized by nonhypertensive cerebral small-vessel arteriopathy with subcortical infarcts, alopecia, and spondylosis, with an onset in early adulthood. On neuropathological examination, atherosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration of the tunica media has been observed in cerebral small arteries.^[3]

Function

[HTRA1_HUMAN] Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.^{[4] [5] [6]}

References

1. ↑ Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006 Nov 10;314(5801):989-92. Epub 2006 Oct 19. PMID:17053108 doi:10.1126/science.1133807
2. ↑ Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006 Nov 10;314(5801):992-3. Epub 2006 Oct 19. PMID:17053109 doi:1133811
3. ↑ Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T, Ikeda M, Shiota H, Tamura M, Shimoe Y, Hirayama M, Arisato T, Yanagawa S, Tanaka A, Nakano I, Ikeda S, Yoshida Y, Yamamoto T, Ikeuchi T, Kuwano R, Nishizawa M, Tsuji S, Onodera O. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009 Apr 23;360(17):1729-39. doi: 10.1056/NEJMoa0801560. PMID:19387015 doi:10.1056/NEJMoa0801560
4. ↑ Hu SI, Carozza M, Klein M, Nantermet P, Luk D, Crowl RM. Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage. J Biol Chem. 1998 Dec 18;273(51):34406-12. PMID:9852107
5. ↑ Grau S, Richards PJ, Kerr B, Hughes C, Caterson B, Williams AS, Junker U, Jones SA, Clausen T, Ehrmann M. The role of human HtrA1 in arthritic disease. J Biol Chem. 2006 Mar 10;281(10):6124-9. Epub 2005 Dec 22. PMID:16377621 doi:10.1074/jbc.M500361200
6. ↑ Campioni M, Severino A, Manente L, Tuduce IL, Toldo S, Caraglia M, Crispi S, Ehrmann M, He X, Maguire J, De Falco M, De Luca A, Shridhar V, Baldi A. The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein. Mol Cancer Res. 2010 Sep;8(9):1248-60. doi: 10.1158/1541-7786.MCR-09-0473. Epub, 2010 Jul 29. PMID:20671064 doi:10.1158/1541-7786.MCR-09-0473
7. ↑ Truebestein L, Tennstaedt A, Monig T, Krojer T, Canellas F, Kaiser M, Clausen T, Ehrmann M. Substrate-induced remodeling of the active site regulates human HTRA1 activity. Nat Struct Mol Biol. 2011 Feb 6. PMID:21297635 doi:10.1038/nsmb.2013