Crystal Structure of the Catalytic Domain of Human ADAM33

Orth, Peter; Reichert, Paul; Wang, Wenyan; Prosise, W.W.; Yarosh-Tomaine, T.; Hammond, Gerald; Ingram, Richard; Xiao, Li; Mirza, Urooj A.; Zou, Jun; Strickland, Corey L.; Taremi, S. Shane; Le, Hung V.; Madison, Vincent

doi:10.1016/j.jmb.2003.10.037

Cited by 84 publications

(87 citation statements)

References 23 publications

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“…1). The X-ray structures of the catalytic domains of ADAM17 and ADAM33 revealed a zinc-binding motif with three conserved histidine residues and a methionine-turn in the active site helix (Maskos et al, 1998;Orth et al, 2004). The catalytic part of ADAMs is characterized by a globular structure with two subdomains and an active cleft between these subdomains (GomisRuth, 2003).…”

Section: Structure and Localization Of Adam Proteasesmentioning

confidence: 99%

Ectodomain shedding and ADAMs in development

Weber¹,

2012

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SummaryProteolytic enzymes belonging to the A Disintegin And Metalloproteinase (ADAM) family are able to cleave transmembrane proteins close to the cell surface, in a process referred to as ectodomain shedding. Substrates for ADAMs include growth factors, cytokines, chemokines and adhesion molecules, and, as such, many ADAM proteins play crucial roles in cell-cell adhesion, extracellular and intracellular signaling, cell differentiation and cell proliferation. In this Review, we summarize the fascinating roles of ADAMs in embryonic and adult tissue development in both vertebrates and invertebrates. Key words: ADAM, Notch, Ectodomain shedding, Cell fate determination, DifferentiationIntroduction Proteins belonging to the 'A Disintegrin And Metalloproteinase' (ADAM) family are membrane-anchored proteases that are able to cleave the extracellular domains of membrane-bound proteins in a process known as 'ectodomain shedding'. Typical substrates of ADAM proteases are growth factors, cytokines, chemokines and their receptors, as well as cell adhesion molecules and differentiation factors (Reiss and Saftig, 2009). ADAMs were initially discovered as novel type I transmembrane proteins with homology to snake venom integrin ligands and that played a functional role during guinea-pig sperm-egg fusion (Blobel et al., 1992). Subsequently, approximately half of the ADAM family members were predicted and then shown to possess zinc-dependent protease activity related to that exhibited by adamalysins metallopeptidases (Wolfsberg et al., 1993; Huxley-Jones et al., 2007). These active 'sheddases ' (ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30 and 33) share a typical consensus sequence (HEXGHXXGXXHD) that is present in zinc-binding proteases (Bode et al., 1993). So far, 40 family members have been identified in the mammalian genome (Puente and Lopez-Otin, 2004; Edwards et al., 2008), of which 37 are expressed in mice (most of them in a testis-specific manner) and 22 are thought to be expressed in humans (Table 1). In both mouse and human, intronless coding sequences probably representing pseudogenes (e.g. human ADAM5P and ADAM6) have also been described. The expression of ADAM or ADAM-related proteins has also been described in many different species, including the yeast Schizosaccharomyces pombe, the nematode worm Caenorhabditis elegans, the frog Xenopus laevis, the zebrafish Danio rerio and the fruitfly Drosophila melanogaster (Alfandari et al., 1997;Nakamura et al., 2004; Huxley-Jones et al., 2007; Iida et al., 2010). It was quickly realized that ADAMs are widely expressed and play fundamental roles during developmental processes, by regulating cell-cell and cell-matrix interactions and by modulating differentiation, migration, receptor-ligand signaling or repulsion (Becherer and Blobel, 2003).Following studies of the catalytically active ADAMs, ectodomain shedding emerged as a central biological event. This proteolytic process primarily affects type I and type II transmembrane proteins, although glycosylphosphatidylinisot...

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Section: Structure and Localization Of Adam Proteasesmentioning

confidence: 99%

Ectodomain shedding and ADAMs in development

Weber¹,

2012

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“…To resolve the importance of cadherin-11 cleavage by ADAMs during CNC migration, we further investigated the effect of blocking ADAM function on this process. We first used a hydroxamate-based inhibitor marimastat that inhibits a wide range of metalloprotease function including ADAMs (Orth et al, 2004). Cos-7 cells transfected with ADAM13 and cadherin-11 were treated with various concentrations of marimastat.…”

Section: Inhibition Of Adam Activity Blocks Cadherin-11 Cleavage In Vivomentioning

confidence: 99%

Extracellular Cleavage of Cadherin-11 by ADAM Metalloproteases Is Essential forXenopusCranial Neural Crest Cell Migration

McCusker

Cousin

Neuner

et al. 2009

MBoC

152

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Cell adhesion molecules such as cadherins alternate their expression throughout cranial neural crest (CNC) development, yet our understanding of the role of these molecules during CNC migration remains incomplete. The "mesenchymal" cadherin-11 is expressed in the CNC during migration yet prevents migration when overexpressed in the embryo, suggesting that a defined level of cadherin-11-mediated cell adhesion is required for migration. Here we show that members of the meltrin subfamily of ADAM metalloproteases cleave the extracellular domain of cadherin-11 during CNC migration. We show that a fragment corresponding to the putative shed form of cadherin-11 retains biological activity by promoting CNC migration in vivo, in a non-cell-autonomous manner. Additionally, cleavage of cadherin-11 does not affect binding to ␤-catenin and downstream signaling events. We propose that ADAM cleavage of cadherin-11 promotes migration by modifying its ability to support cell-cell adhesion while maintaining the membrane-bound pool of ␤-catenin associated with the cadherin-11 cytoplasmic domain.

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“…VAP-1, as shown in Fig. 1D) (23)(24)(25)(26). These domains can be superimposed to the ADAM22 domain M with an r.m.s.…”

Section: Adam22 Expression and Propeptidementioning

confidence: 93%

“…Although ADAMs are functionally important as sheddases or adhesion receptors, the structural information about the ADAM family is limited to only isolated domains, such as the metalloproteinase domains of ADAM17 and ADAM33 and the incomplete disintegrin cysteine-rich domains of ADAM10 (21)(22)(23). Their relatives, SVMPs from the snake venom, including VAP-1, VAP-2, and RVV-X (24 -26), have revealed a "C"-shaped molecular architecture.…”

mentioning

confidence: 99%

Structural Characterization of the Ectodomain of a Disintegrin and Metalloproteinase-22 (ADAM22), a Neural Adhesion Receptor Instead of Metalloproteinase

Liu

Shim

2009

Journal of Biological Chemistry

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ADAMs (a disintegrin and metalloproteinases) are a family of multidomain transmembrane glycoproteins with diverse roles in physiology and diseases, with several members being drug targets for cancer and inflammation therapies. The spatial organization of the ADAM extracellular segment and its influence on the function of ADAMs have been unclear. Although most members of the ADAM family are active zinc metalloproteinases, 8 of 21 ADAMs lack functional metalloproteinase domains and are implicated in protein-protein interactions instead of membrane protein ectodomain shedding. One of such non-proteinase ADAMs, ADAM22, acts as a receptor on the surface of the postsynaptic neuron to regulate synaptic signal transmission. The crystal structure of the full ectodomain of mature human ADAM22 shows that it is a compact four-leaf clover with the metalloproteinase-like domain held in the concave face of a rigid module formed by the disintegrin, cysteinerich, and epidermal growth factor-like domains. The loss of metalloproteinase activity is ensured by the absence of critical catalytic residues, the filling of the substrate groove, and the steric hindrance by the cysteine-rich domain. The structure, combined with calorimetric experiments, suggests distinct roles of three putative calcium ions bound to ADAM22, with one in the metalloproteinase-like domain being regulatory and two in the disintegrin domain being structural. The metalloproteinase-like domain contacts the rest of ADAM22 with discontinuous, hydrophilic, and poorly complemented interactions, suggesting the possibility of modular movement of ADAM22 and other ADAMs. The ADAM22 structure provides a framework for understanding how different ADAMs exert their adhesive function and shedding activities.The ADAM 2 family includes over 20 multidomain type I transmembrane glycoproteins that have diverse functions in cell adhesion/signaling and ectodomain shedding of cell-surface receptors or ligands (1, 2). They are broadly implicated in various physiological processes including sperm-egg interactions, development and function of the nervous system (e.g. cell-fate determination, axon guidance, and myelination), immune responses, and embryogenesis (2, 3). Dysregulation of the ADAM family is linked to a wide variety of pathological states including cancer, cardiovascular disease, asthma, Alzheimer disease, and inflammation (3-5). Several ADAMs have been pursued as therapeutic targets (6, 7).ADAMs, together with their phylogenic relatives, the P-III class snake venom metalloproteinases (SVMPs) and ADAMTSs (ADAM with thrombospondin type-1 motif), constitute a subgroup of the metzincin clan of zinc proteinases (8, 9). The extracellular segments of ADAMs contain a prodomain that gets cleaved off during secretion, a metalloproteinase-like domain, a disintegrin domain, and a cysteine-rich domain, which are shared by SVMPs and ADAMTSs, and a unique epidermal growth factor-like domain preceding the transmembrane segment. All ADAMs contain metalloproteinase-like domains, but in humans...

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Crystal Structure of the Catalytic Domain of Human ADAM33

Cited by 84 publications

References 23 publications

Ectodomain shedding and ADAMs in development

Ectodomain shedding and ADAMs in development

Extracellular Cleavage of Cadherin-11 by ADAM Metalloproteases Is Essential forXenopusCranial Neural Crest Cell Migration

Structural Characterization of the Ectodomain of a Disintegrin and Metalloproteinase-22 (ADAM22), a Neural Adhesion Receptor Instead of Metalloproteinase

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