ADAMTS proteins in human disorders.
ADAMTS proteins in human disorders.
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DOI：
10.1016/j.matbio.2018.06.002
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Apte SS
中科院分区：
文献类型：
--
作者：
Mead TJ;Apte SS
ADAMTS蛋白是一个由26种分泌分子组成的超家族，包括两个相关但不同的家族。ADAMTS蛋白酶是锌金属内肽酶，其大多数底物是细胞外基质（ECM）组分，而ADAMTS样蛋白缺乏金属蛋白酶结构域，存在于ECM中，并维斯ECM组装和/或ADAMTS活性具有调节作用。ADAMTS蛋白在哺乳动物中的进化保守性和扩展性提示了其在人类胚胎学或生理学中的重要作用。事实上，由天然存在的ADAMTS 2、ADAMTS 3、ADAMTS 10、ADAMTS 13、ADAMTS 17、ADAMTS 20、ADAMTSL 2和ADAMTSL 4突变以及在基因工程小鼠中鉴定的许多表型引起的孟德尔疾病或出生缺陷已经揭示了ADAMTS参与主要生物学途径。重要的作用已经确定在一些后天条件。ADAMTS 5通过降解软骨中的主要结构蛋白聚糖聚集蛋白聚糖明确参与骨关节炎的发病机制。ADAMTS 7与冠状动脉疾病密切相关，并促进动脉粥样硬化。ADAMTS 13自身抗体导致血小板凝血病，血栓性血小板减少性紫癜，这与ADAMTS 13突变导致的血小板凝血病相似。ADAMTS蛋白与全基因组关联研究确定的其他人类疾病有许多潜在联系。本文就ADAMTS蛋白参与的人类遗传性和获得性疾病进行综述，并讨论其治疗进展和前景。
ADAMTS proteins are a superfamily of 26 secreted molecules comprising two related, but distinct families. ADAMTS proteases are zinc metalloendopeptidases, most of whose substrates are extracellular matrix (ECM) components, whereas ADAMTS-like proteins lack a metalloprotease domain, reside in the ECM and have regulatory roles vis-à-vis ECM assembly and/or ADAMTS activity. Evolutionary conservation and expansion of ADAMTS proteins in mammals is suggestive of crucial embryologic or physiological roles in humans. Indeed, Mendelian disorders or birth defects resulting from naturally occurring ADAMTS2, ADAMTS3, ADAMTS10, ADAMTS13, ADAMTS17, ADAMTS20, ADAMTSL2 and ADAMTSL4 mutations as well as numerous phenotypes identified in genetically engineered mice have revealed ADAMTS participation in major biological pathways. Important roles have been identified in a few acquired conditions. ADAMTS5 is unequivocally implicated in pathogenesis of osteoarthritis via degradation of aggrecan, a major structural proteoglycan in cartilage. ADAMTS7 is strongly associated with coronary artery disease and promotes atherosclerosis. Autoantibodies to ADAMTS13 lead to a platelet coagulopathy, thrombotic thrombocytopenic purpura, which is similar to that resulting from ADAMTS13 mutations. ADAMTS proteins have numerous potential connections to other human disorders that were identified by genome-wide association studies. Here, we review inherited and acquired human disorders in which ADAMTS proteins participate, and discuss progress and prospects in therapeutics.
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