Crystal structure of archaemetzincin amza from <i>Methanopyrus kandleri</i> at 1.5 Å resolution

Waltersperger, S.; Widmer, Christine; Wang, Meitian; Baumann, Ulrich

doi:10.1002/prot.22777

Cited by 12 publications

(20 citation statements)

References 23 publications

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“…It is likely that an archaelysin most closely represents the ancestral Met-zincin structure. Archaelysin possesses the Met-turn [40,41], so the implication is that the Met-turn has been lost from an ancestor of family M94 and functionally replaced by a C-terminal aromatic residue (tyrosine or phenylalanine). The much narrower distribution of members of M94 supports the hypothesis that the family is a more recent development.…”

Section: Resultsmentioning

confidence: 99%

New mini- zincin structures provide a minimal scaffold for members of this metallopeptidase superfamily

et al. 2014

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BackgroundThe Acel_2062 protein from Acidothermus cellulolyticus is a protein of unknown function. Initial sequence analysis predicted that it was a metallopeptidase from the presence of a motif conserved amongst the Asp-zincins, which are peptidases that contain a single, catalytic zinc ion ligated by the histidines and aspartic acid within the motif (HEXXHXXGXXD). The Acel_2062 protein was chosen by the Joint Center for Structural Genomics for crystal structure determination to explore novel protein sequence space and structure-based function annotation.ResultsThe crystal structure confirmed that the Acel_2062 protein consisted of a single, zincin-like metallopeptidase-like domain. The Met-turn, a structural feature thought to be important for a Met-zincin because it stabilizes the active site, is absent, and its stabilizing role may have been conferred to the C-terminal Tyr113. In our crystallographic model there are two molecules in the asymmetric unit and from size-exclusion chromatography, the protein dimerizes in solution. A water molecule is present in the putative zinc-binding site in one monomer, which is replaced by one of two observed conformations of His95 in the other.ConclusionsThe Acel_2062 protein is structurally related to the zincins. It contains the minimum structural features of a member of this protein superfamily, and can be described as a “mini- zincin”. There is a striking parallel with the structure of a mini-Glu-zincin, which represents the minimum structure of a Glu-zincin (a metallopeptidase in which the third zinc ligand is a glutamic acid). Rather than being an ancestral state, phylogenetic analysis suggests that the mini-zincins are derived from larger proteins.

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Section: Resultsmentioning

confidence: 99%

New mini- zincin structures provide a minimal scaffold for members of this metallopeptidase superfamily

et al. 2014

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“…Metzincin exceptions lacking prosegments include the archaemetzincins, for which no hydrolytic activity has so far been reported, i.e. they might not need to be kept latent (41,42); the toxilysin EcxA from Escherichia coli, whose soluble expression requires co-expression with its cognate EcxB subunit, thus pointing to a chaperone-like function for this ancillary subunit (43)(44)(45); the cholerilysin StcE from E. coli, for which an N-terminal immunoglobulin-like domain may assist the downstream catalytic moiety in proper folding (46); and igalysins, where an all-␤-domain of similar topology to immunoglobulin-like domains is likewise found at the N terminus of the catalytic moiety (see Protein Data Bank (PDB) access codes 4DF9 and 3P1V and Ref. 5).…”

Section: X-x-h-x-x-(g/n)-x-x-(h/d)mentioning

confidence: 99%

A Novel Mechanism of Latency in Matrix Metalloproteinases

López-Pelegrín

Książek

Karim

et al. 2015

Journal of Biological Chemistry

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Background: Animal and plant matrix metalloproteinases (MMPs) are kept zymogenic through large prodomains and a cysteine-switch mechanism. Results: Bacterial MMP karilysin has only a short N-terminal peptide upstream of the catalytic domain, which lacks cysteines. Conclusion: This peptide inhibits through an aspartate-switch mechanism and also exerts other functions of authentic prodomains. Significance: Karilysin is kept latent by a novel mechanism for MMPs.

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“…The rest of the CTS is characterized by few regular secondary structure elements, and only three short 3 10 -helices ( η 1 -η 3) and two short strands ( β 6 and β 7) are found in addition to the major ' C-terminal helix ' ( α C; Figure 2B). Special mention should be given to a tight 1,4-turn situated below the catalytic zinc-site, the Met-turn, which is characterized by a strictly conserved methionine (M 147 ), both in sequence and side-chain conformation, within astacins and also all other metzincins structurally analyzed to date (Gomis -R ü th, 2009 ; Goulas et al , 2010 ;Waltersperger et al , 2010 ). It has been proposed that the Met-turn acts as a plug that inserts laterally into a core structure created by the protein segment engaged in zinc binding, thus contributing to the structural integrity that is indispensable for function, but there is still debate on its signifi cance in metzincins (Pieper et al , 1997 ;Boldt et al , 2001 ;Hege and Baumann , 2001 ;Butler et al , 2004 ;Walasek and Honek , 2005 ;P é rez et al, 2007 ;Oberholzer et al , 2009 ;Tallant et al , 2010a ).…”

Section: Overall Structure Of Mature Astacin Catalytic Domainsmentioning

confidence: 99%

Functional and structural insights into astacin metallopeptidases

Gomis‐Rüth

Trillo-Muyo

Stöcker

2012

Biological Chemistry

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The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by being synthesized as inactive zymogens and also by colocalizing protein inhibitors. The distinct family members consist of N-terminal signal peptides and pro-segments, zincdependent catalytic domains, further downstream extracellular domains, transmembrane anchors, and cytosolic domains. The catalytic domains of four astacins and the zymogen of one of these have been structurally characterized and shown to comprise compact ∼ 200-residue zinc-dependent moieties divided into an N-terminal and a C-terminal sub-domain by an active-site cleft. Astacins include an extended zinc-binding motif (HEXXHXXGXXH) which includes three metal ligands and groups them into the metzincin clan of metallopeptidases. In mature, unbound astacins, a conserved tyrosine acts as an additional zinc ligand, which is swung out upon substrate or inhibitor binding in a ' tyrosine switch ' motion. Other characteristic structural elements of astacin catalytic domains are three large α -helices and a fi ve-stranded β -sheet, as well as two or three disulfi de bonds. The N-terminal pro-segments are variable in length and rather unstructured. They inhibit the catalytic zinc following an ' aspartate-switch ' mechanism mediated by an aspartate embedded in a conserved motif (FXGD). Removal of the pro-segment uncovers a deep and extended active-site cleft, which in general shows preference for aspartate residues in the specifi city pocket (S 1 ′ ). Furthermore, astacins undergo major rearrangement upon activation within an ' activation domain, ' and show a slight hinge movement when binding substrates or inhibitors. In this review, we discuss the overall architecture of astacin catalytic domains and their involvement in function and zymogenic activation.

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Crystal structure of archaemetzincin amza from Methanopyrus kandleri at 1.5 Å resolution

Cited by 12 publications

References 23 publications

New mini- zincin structures provide a minimal scaffold for members of this metallopeptidase superfamily

New mini- zincin structures provide a minimal scaffold for members of this metallopeptidase superfamily

A Novel Mechanism of Latency in Matrix Metalloproteinases

Functional and structural insights into astacin metallopeptidases

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