Many membrane proteins undergo ectodomain shedding by proteolytic cleavage. Does one sheddase do the job on all of these proteins?

Is There An Answer? is intended to serve as a forum in which readers to IUBMB Life may pose questions of the type that intrigue biochemists but for which there may be no obvious answer or one may be available but not widely known or easily accessible.Readers are invited to e-mail ascenzi@uniroma3.itif they have questions to contribute or if they can provide answers to questions that are provided here from time to time.In the latter case, instructions will be sent to interested readers.Answers should be, whenever possible, evidence-based and provide relevant references.-Paolo Ascenzi Ectodomain shedding is the release of the extracellular domain of a membrane protein by proteolysis (1 -3).This process and the proteases involved, called sheddases, control the biological activity of membrane proteins.It occurs in nonstimulated cells and is called basal shedding but it is dramatically activated by several independent mechanisms (1).The diversity of proteins that undergo ectodomain shedding indicates that the process is essential not only during normal mammalian development but also in pathological conditions including inflammation, cancer, rheumatoid arthritis and Alzheimer disease (4 -7).At the cellular level, sheddases control cell adhesion, signal transduction, the release of cytokines and growth factors, and generation of the b-amyloid peptide (b-AP) from b-amyloid precursor protein (b-APP) in Alzheimer disease (4, 7, 8).The two major groups of proteases involved in ectodomain shedding are the metalloproteinase disintegrin (ADAM, which stands for 'a disintegrin and metalloproteinase') and matrix metalloproteinase (MMP) families (1).ADAMs are transmembrane proteins that contain a disintegrin, a catalytic domain and an epidermal growth factor (EGF)-like domain.The first protease identified in ectodomain shedding was tumor necrosis factor (TNF)-a converting enzyme (TACE) or ADAM-17, a protein of 85 kDa.T-cells derived from mice that were genetically deficient in the zinc-binding domain of TACE (tace 7/7 cells) showed an 80 -90% reduction in TNF-a shedding compared to wild type (9).TACE was found to cleave the Ala 76 -Val 77 bond on pro-TNF-a (10).Currently, 18 of the 33 identified ADAMs are predicted to function as proteases, while the rest are not likely to be active proteases since they lack the consensus Zn-binding domain.Arribas and Borroto (1) hypothesized that, since many ADAMs are involved in ectodomain shedding, each may be endowed with a restricted specificity.According to this hypothesis, TACE would only be responsible for the shedding of TNF-a, but not of other unrelated molecules.However, the situation seems to be much more complex.For instance, shedding of structural and functional transmembrane molecules such as TNF-a, interleukin-1 receptor II and b-APP is severely impaired in (tace 7/7 cells) showing that all have a requirement for TACE (7,9,11,12).Experiments performed using cell cultures showed that recombinant TACE catalytic domain cleaves the Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala region of b-APP at the Lys-Leu bond, which coincides with a-secretase cleavage site on b-APP.Thus, TACE and asecretase may have common substrates such as b-APP (7, 13, 14), thus supporting the notion that TACE may act on more substrates than initially thought.In vitro substrate-protease matching experiments that involve the cotransfection of substrates with their suspected protease or a dominant negative version of it have identified pro-heparin-binding EGF (pro-HB-EGF) and b-APP as possible substrates of ADAM-9, a protein of 90.5 kDa (15, 16).However, this may not be the case in vivo.Fibroblasts isolated from ADAM-9 knock-out mice do not show a significant difference in the levels of pro-HB-EGF or b-APP compared to wild type fibroblasts stimulated by phorbol esters

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.