Structure of human ADAM-8 catalytic domain complexed with batimastat

Hall, Troii; Shieh, Huey‐Sheng; Day, Jacqueline E.; Caspers, Nicole; Chrencik, Jill E.; Williams, Jennifer M.; Pegg, Lyle E.; Pauley, Adele M.; Moon, A.F.; Krahn, J.M.; Fischer, D.H.; Kiefer, James R.; Tomasselli, Alfredo G.; Zack,

doi:10.1107/s1744309112015618

Cited by 11 publications

(7 citation statements)

References 37 publications

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“…16 Consistent with the report by Zack et al, we identified multiple bands reactive with the anti-ADAM8 antibody in IVD tissues. 16 Future investigations of ADAM-8 inhibitors such as batimastat 22 might lead to interventions that would prevent FN fragmentation thus delay IVD degeneration.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin Fragments and the Cleaving Enzyme ADAM-8 in the Degenerative Human Intervertebral Disc

Ruel

Markova

Adams

et al. 2014

Spine

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Study Design The presence fibronectin fragments (FN-fs) and the cleaving enzyme, A disintegrin and metalloproteinase domain-containing protein (ADAM)-8 were examined in human intervertebral disc (IVD) tissue in vitro. Objective To investigate the presence and pathophysiological concentration of FN-fs and their cleaving enzyme, ADAM-8, in the human IVD tissue. Summary of Background Data The 29kDa FN-f has been shown to result in extracellular matrix loss in rabbit IVDs. However, the concentration of this biologically active fragment in the degenerative human IVD tissue has previously not been determined. Further, it is critical to identify the enzyme(s) responsible for FN cleavage in the IVD. Methods Human degenerative IVD tissues were removed during spinal surgery. A normal appearing young adult and an infant human cadaveric sample were obtained as controls. Soluble proteins were extracted, and analyzed by Western blotting utilizing antibodies specific for the human FN neoepitope VRAA271. A purified 29 kDa FN-f was used to allow estimation of the concentration of FN-fs in the tissues. ADAM-8, a FN-cleaving enzyme, was analyzed by Western blotting and immunostaining. Results All adult IVD tissues contain many FN-f species, but these species were absent from the infant disc tissue. Moderately degenerative discs contained the highest amount of FN-fs; the concentration was estimated to be in the nanomolar range per gram of tissue. ADAM-8, known to cleave FN resulting in the VRAA271 neoepitope, was present in the human disc. ADAM-8 primarily localized in the pericellular matrix of the nucleus pulposus (NP) tissue, as determined by immunostaining. Conclusion This is the first report that N-terminal FN-fs are consistently present in IVD tissues from adult subjects. The pathophysiological concentration of these fragments is estimated to be at nanomolar range per gram of IVD tissue. Further, ADAM-8, known to cleave FN, is present at the pericellular matrix of disc cells.

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Section: Discussionmentioning

confidence: 99%

Fibronectin Fragments and the Cleaving Enzyme ADAM-8 in the Degenerative Human Intervertebral Disc

Ruel

Markova

Adams

et al. 2014

Spine

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“…The currently available M domain structures of ADAMs, ADAMTSs and all classes of SVMPs are very similar to each other, although comparison of the amino acid sequences of various members shows high variability (typically 20%–50% identity). Interestingly, although the human ADAM8 M domain is most similar in sequence to the human ADAM33 M domain (44% identity), its crystal structure is most similar to that of P-I SVMP adamalysin II [ 68 ]. The M domain of the non-catalytic ADAM22 also adopts a very similar backbone structure to those of other catalytic ADAMs, ADAMTs and SVMPs [ 65 ].…”

Section: Three-dimensional Structuresmentioning

confidence: 99%

ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview

Takeda

2016

Toxins

126

115

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A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major components in most viper venoms. SVMPs are primarily responsible for hemorrhagic activity and may also interfere with the hemostatic system in envenomed animals. SVMPs are phylogenetically most closely related to ADAMs and, together with ADAMs and related ADAM with thrombospondin motifs (ADAMTS) family proteinases, constitute adamalysins/reprolysins or the M12B clan (MEROPS database) of metalloproteinases. Although the catalytic domain structure is topologically similar to that of other metalloproteinases such as matrix metalloproteinases, the M12B proteinases have a modular structure with multiple non-catalytic ancillary domains that are not found in other proteinases. Notably, crystallographic studies revealed that, in addition to the conserved metalloproteinase domain, M12B members share a hallmark cysteine-rich domain designated as the “ADAM_CR” domain. Despite their name, ADAMTSs lack disintegrin-like structures and instead comprise two ADAM_CR domains. This review highlights the current state of our knowledge on the three-dimensional structures of M12B proteinases, focusing on their unique domains that may collaboratively participate in directing these proteinases to specific substrates.

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“…Homology Modeling of the hADAMEC1 Structure-To gain insight into how the rare and unique features of the ADAMDEC1 amino acid sequence may impact the structure of ADAMDEC1, a homology model was created using the crystal structures of hADAM-8, hADAM-22, and snapalysin as templates (23,24,26). The metalloprotease domain was modeled after the hADAM-8 structure; the active site was based on snapalysin and refined by energy minimization.…”

Section: Timps Do Not Inhibit Adamdec1 But N-timp-3 Inhibits Adamdecmentioning

confidence: 99%

Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

Lund

Troeberg

Kjeldal

et al. 2015

Journal of Biological Chemistry

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Background: ADAMDEC1 is an ADAM-like metalloprotease with a rare active site affecting the proteolytic activity. Results: Reconstruction of the ADAMDEC1 active site, based on the ADAM family consensus, increases proteolytic activity and susceptibility for inhibition. Conclusion: Specific structural features may protect ADAMDEC1 from endogenous metalloprotease inhibitors. Significance: ADAMDEC1 has evolved features resulting in narrow substrate specificity and restricted reactivity with endogenous protease inhibitors.

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Structure of human ADAM-8 catalytic domain complexed with batimastat

Cited by 11 publications

References 37 publications

Fibronectin Fragments and the Cleaving Enzyme ADAM-8 in the Degenerative Human Intervertebral Disc

Fibronectin Fragments and the Cleaving Enzyme ADAM-8 in the Degenerative Human Intervertebral Disc

ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview

Evidence for Restricted Reactivity of ADAMDEC1 with Protein Substrates and Endogenous Inhibitors

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