Serralysiiniperhe (ihmisvihollisia), Virulenssiproteiinisetti

https://www.researchgate.net/figure/Phylogenetic-linkage-of-ZapA-to-the-serralysin-family-of-zinc-metalloproteases-Analysis_fig2_15607465
 

Phylogenetic linkage of ZapA to the serralysin family of zinc metalloproteases. Analysis of the deduced amino acid sequence of ZapA indicates the presence of several signature peptide motifs that are held in common with many other homologous metalloproteases belonging to the serralysin family of metalloproteases, including the proteases of S. marcescens, E. chrysanthemi, P. aeruginosa, and (from this research) P. mirabilis. 

The serralysin family has the zinc metalloprotease domain, the Met turn of metzincins, and three or more Ca 2 binding motifs, and all are exported by a COOH terminal secretory signal. The serralysin family of zinc metalloproteases is in turn part of a larger set of proteins thought to function as virulence factors in several genera of bacteria. 

This set of virulence proteins includes

 Actinobacillus (Haemophilus) pleuropneumoniae hemolysin protein, AppA (18), 

Actinobacillus suis AppA (17), 

Pasteurella haemolytica LktA leukotoxin (20),

 enterohemorrhagic E. coli HlyA hemolysin (33), 

Actinobacillus actinomycetemcomitans LktA leukotoxin (40, 41),

 Bordetella pertussis adenylate cyclase CyaA (16), 

N. meningitidis Fe-regulated RTX cytotoxin homolog (FrpA) (64),

 and Pseudomonas fluorescens lipase LipA (27, 63).

 All of these proteins have the common feature of the Ca 2 binding GGXGXD repeat motif among other characteristics. 

The phylogenetic linkage map was established from nucleotide and amino acid sequences stored in the GenBank, EMBL, and Pir libraries and was analyzed with the Genetics Computer Group program PILEUP.

....
 . One of these factors, ZapA metalloprotease, is of distinctive significance. It is an IgA-degrading protease that is specifically expressed during differentiation of swimmer into swarmer cells ( Wassif et al., 1995). Now-a-days due to increasing antibiotic resistance in Enterobacteriaceae, the multidrug resistant (MDR) strains of Proteus species have also been reported worldwide. ...

Serralysiinin kaltaisten  metalloproteaasien C-terminaalin piirteitä: 

https://www.ebi.ac.uk/interpro/entry/InterPro/IPR011049/

serralysin MeSH Supplementary Concept Data 2020

• Details
• Concepts

MeSH Supplementary

serralysin

Unique ID

C095666

RDF Unique Identifier

http://id.nlm.nih.gov/mesh/C095666

Registry Number

EC 3.4.24.40

Heading Mapped to

*Metalloendopeptidases

Frequency

47

Note

zinc metalloproteinases with broad similar specificity for cleavage of the oxidized insulin B chain

Source

Methods Enzymol 1995;248:395-413

Date of Entry

1995/10/17

Revision Date

2004/08/06

 

Metzinkiiniperheen ( klaani MA) tietoa 2009: metioniinia sisältävä Met-turn ja pitkä sinkkiä sitova konsensusmotiivi

J Biol Chem. 2009 Jun 5;284(23):15353-7. doi: 10.1074/jbc.R800069200. Epub 2009 Feb 5.Catalytic domain architecture of metzincin metalloproteases.

Gomis-Rüth FX¹. Abstract

Metalloproteases cleave proteins and peptides, and deregulation of their function leads to pathology. An understanding of their structure and mechanisms of action is necessary to the development of strategies for their regulation. Among metallopeptidases are the metzincins, which are mostly multidomain proteins with approximately 130-260-residue globular catalytic domains showing a common core architecture characterized by a long zinc-binding consensus motif, HEXXHXXGXX(H/D), and a methionine-containing Met-turn.
 Metzincins participate in unspecific protein degradation such as digestion of intake proteins and tissue development, maintenance, and remodeling, but they are also involved in highly specific cleavage events to activate or inactivate themselves or other (pro)enzymes and bioactive peptides. Metzincins are subdivided into families, and seven such families have been analyzed at the structural level:
the astacins,
ADAMs/adamalysins/reprolysins,
serralysins,
 matrix metalloproteinases,
 snapalysins,
leishmanolysins, and
 pappalysins.
These families are reviewed from a structural point of view.

DOI:

10.1074/jbc.R800069200

[Indexed for MEDLINE]

2020 katson uusinta tietoa serralysiineistä.

 

2013   tietoa

Serralysin and Related Enzymes

Ulrich Baumann, in Handbook of Proteolytic Enzymes (Third Edition), 2013

Name and History

Serralysin was first discovered in the culture medium of Serratia sp. E-15 [1] and was named from the genus name Serratia+lysin. Similar proteases have been found to be secreted by other Gram-negative bacteria, e.g. Pseudomonas aeruginosa [2] and Erwinia chrysanthemi [3–6], Ps. fluorescens [7,8], or Photorhabdus luminescens [9]. These proteases are quite similar in their physicochemical properties and are grouped together in the serralysin subfamily. Later, it was established on evidence from three-dimensional structures that serralysins, together with matrix metalloproteases, astacins and snake venom proteinases, belong to clan MA (the metzincins) [10].

Serralysiiniperhe Metzinkiinisuperperheessä. Esimerkki. vuodelta 1999.

Biosci Biotechnol Biochem. 1999 Jul;63(7):1165-70.

Identification of a member of the serralysin family isolated from a psychrotrophic bacterium, Pseudomonas fluorescens 114.

Kumeta H¹, Hoshino T, Goda T, Okayama T, Shimada T, Ohgiya S, Matsuyama H, Ishizaki KAbstract

An extracellular metalloprotease named No. 114 protease is one of the major secretions of a psychrotrophic bacterium, Pseudomonas fluorescens 114, the cold-adaptation mechanism of which has not been identified. In this study, we purified and cloned No. 114 protease, which is a single polypeptide having a molecular mass of 47 kDa. This protease contains a zinc-binding motif (HEXXHXUGUXH: X, arbitrary amino acid; U, bulky hydrophobic amino acid), glycine-rich repeats (GGXGXD) and no cysteine residue, which are the features specifically found in serralysin subfamily. No. 114 protease has its maximum activity at the temperature of 35-40 degrees C, which is about 20 degrees C lower than that of a serralysin from a mesophilic bacterium, Pseudomonas aeruginosa. All these results imply that No. 114 protease from this psychrophilic bacterium is a unique member of the serralysin group characterized by a low optimal temperature.

PMID:

10478443

DOI:

10.1271/bbb.63.1165

[Indexed for MEDLINE]

Free full text

METZINCIN- superfamily -kartta.

https://www.researchgate.net/figure/The-metzincin-gene-family-A-Schematic-representation-of-subdivisions-within-the_fig1_6388280

Tässä Met viitaa methionine- aminohappoon, joka  propeptidissä merkitsee  Met turn- kohdan muodostumista  tiukka  silmukkaan  (" tigh hair pin loop", jossa  propeptidin alueella sijaitseva C ja aktiivin kohdan alueen  3 histidiinin (H) kesken  koordinoituu Zn++ siten, että aktiivi kohta esittytyy. 
 

4-siipinen propelli on hemopexiinin kaltaisten proteiinien superperheessä , kuten usealla MMP- proteiinilla

MMP1 (11q22.2) sinkistä riippuva MMP, ZnMc matrilysiini domeenin ja HX propellin omaava. Hemopexiinitoistoa 4-siipi propellina

1. ORIGIN 1 mqeffglkvt gkpdaetlkv MkqPRCGVPD vaqfvltegn prweqthlty rienytpdlp
   

          61 radvdhaiek afqlwsnvtp ltftkvsegq adimisfvrg dhrdnspfdg pggnlahafq
         121 pgpgiggdah fdederwtnn freynlhrva aHElgHslgl sHstdigalm ypsytfsgdv
         181 qlaqddidgi qaiygrsqnp vqpigpqtpk acdskltfda ittirgevmf fkdrfymrtn
         241 pfypevelnf isvfwpqlpn gleaayefad rdevrffkgn kywavqgqnv lhgypkdiys
         301 sfgfprtvkh idaalseent gktyffvank ywrydeykrs mdpgypkmia hdfpgighkv
         361 davfmkdgff yffhgtrqyk fdpktkrilt lqkanswfnc rkn
   //

    (Tästä mtixmetalloproteiinista on useita  artikkeleita PubMed lähteestä vuodelta 2019. Nyt katson nitä MMP- molekyylejäuudestaan. ne ovat sinkistä riippuvaisia. Katalyyttisessä kohdassa on  Zn ja Hemopexiinipropelli koordinoi  Zn tai Calsiumia.
   Signaalipeptidin jälkeen  oleva propeptidio on n 80 aminoappoa ja siinä on tunnusomaista konservatiivinen sekvenssi PRCG(C/N)PD, tässä  peptidissä se on 24..30  kohdalla. Siinä näkyvä cysteiini(C)  kiinnitty katalyyttisen domeenin Zn metalliin ja pitää täten yllä  MMP-proteiinin latenssitilaa , propeptidimuotoa (pro-MMP). 
   Katalyyttinen kohta on 42..195, " ZnMc_MMP.  Siinä on sinkkiä sitova kohta jakson keskellä motiivissa HEXXHXUGUXH, (U tarkoittaa hydrofobista bulk-aminohappoa) .  
   H152, E153, H156, H162.  
   C-terminaalissa päin oleva hemopexiini moduli (HX toistoja 4) , 4-siipinen propelli, jota sitoutuneet metallit pitävät koossa  2-siipinen  propelli,   sinkkia tai  kalsiumia metallina.  
    (Hemopexin-like superfamily- tunnus)
   NM_001145938.2 → NP_001139410.1  interstitial collagenase isoform 2
   See identical proteins and their annotated locations for NP_001139410.1
   
   Status: REVIEWED

   Description

   Transcript Variant: This variant (2) uses an alternate in-frame splice site in the 5' coding region and uses a downstream start codon compared to variant 1. The resulting protein (isoform 2) has a shorter N-terminus compared to isoform 1.

   Source sequence(s)

   AK297723, AP000619

   UniProtKB/TrEMBL

   B4DN15

   Conserved Domains (4) summary

   cd00094
   Location:209 → 400

   HX; Hemopexin-like repeats.; Hemopexin is a heme-binding protein that transports heme to the liver. Hemopexin-like repeats occur in vitronectin and some matrix metalloproteinases family (matrixins). The HX repeats of some matrixins bind tissue inhibitor of  metalloproteinases (TIMPs). This CD contains 4 instances of the repeat.

    

   cd04278
   Location:42 → 195

   weqthlty rienytpdlp
          61 radvdhaiek afqlwsnvtp ltftkvsegq adimisfvrg dhrdnspfdg pggnlahafq
         121 pgpgiggdah fdederwtnn freynlhrva ahelghslgl shstdigalm ypsytfsgdv
         181 qlaqddidgi qaiyg

   ZnMc_MMP; Zinc-dependent metalloprotease, matrix metalloproteinase (MMP) sub-family. MMPs are responsible for a great deal of pericellular proteolysis of extracellular matrix and cell surface molecules, playing crucial roles in morphogenesis, cell fate ..specification, cell migration, tissue repair, tumorigenesis, gain or loss of tissue-specific functions, and apoptosis. In many instances, they are anchored to cell membranes via trans-membrane domains, and their activity is controlled via TIMPs (tissue inhibitors of metalloproteinases).

   Feature 1:active site [active site]

   Evidence:

   • Comment:consensus motif: HEXXHXUGUXH U= bulky hydrophobic
   • Comment:coordinates zinc, contains catalytic Glu
   • Citation:PMID 8253063
   • Structure:1BQQ: Human type-1 matrix metalloprotease coordinates zinc
     - View structure with Cn3D
   • Citation:PMID 9724659

    

    

   pfam00413

    
   Location:42 → 195

   Peptidase_M10; MatrixinThe members of this family are enzymes that cleave peptides. These proteases require zinc for catalysis.

   pfam01471
   Location:1 → 21

   PG_binding_1; Putative peptidoglycan binding domainThis domain is composed of three alpha helices. This domain is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation. .. This domain may have a general peptidoglycan binding function. This family is found N-terminal to the catalytic domain of matrixins. The domain is found to bind peptidoglycan experimentally.

    
   

Matrixmetalloproteinaasit omaavat sinkkiä sitovan kohdan, jota inhibiittori käyttää hyödyksi.

https://www.ncbi.nlm.nih.gov/pubmed/15723627

Curr Pharm Des. 2005;11(3):295-322.

Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies.

Rao BG¹.

Abstract

It has been 10 years since a 3-dimensional structure of the catalytic domain of a Matrix Metalloprotease (MMP) was revealed for the first time in 1994. More than 80 structures of different MMPs in apo and inhibited forms, determined by X-ray crystallography and NMR methods, have been published by the end of year 2003. A large number of very potent inhibitors have been disclosed in published and patent literature. Several MMP inhibitors entered clinical trials for the treatment of cancer and arthritis. Most of the first generation inhibitors have hydroxamic acid as the Zinc-binding group and have limited specificity. With the failure of these inhibitors in clinical trials, more efforts have been directed to the design of specific inhibitors with different Zn-binding groups in recent years. This review will summarize all the published structural information and focus on the inhibitors that were designed to take advantage of the nonprime side of the MMP active site using structural information and computational analysis. Representative structures from all MMPs are aligned to a target structure to provide a better understanding of the similarities and differences of the active site pockets. This analysis supports the view that the differences in the nonprime side pockets provide better opportunities for designing inhibitors with higher specificity. Published information on all the Zinc-binding groups of MMP inhibitors is reviewed for the first time. Pros and cons of inhibitors with non-hydroxamate Zinc-binding groups in terms of specificity, toxicity and pharmacokinetic properties are discussed.

PMID:

15723627

DOI:

10.2174/1381612053382115

[Indexed for MEDLINE]