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4dcb

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4dcb, resolution 2.03Å ()
Ligands: , , ,
Gene: pla, YPPCP1.07, YP_pPCP08 (Yersinia pestis)
Activity: Plasminogen activator Pla, with EC number 3.4.23.48


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Y. pestis Plasminogen Activator Pla in Complex with Human Plasminogen Activation Loop Peptide ALP11

Publication Abstract from PubMed

Omptins constitute a unique family of outer membrane proteases that are widespread in Enterobacteriaceae. The plasminogen activator (Pla) of Yersinia pestis is an omptin family member that is very important for development of both bubonic and pneumonic plague. The physiological function of Pla is to cleave (activate) human plasminogen to form the plasma protease plasmin. Uniquely, lipopolysaccharide (LPS) is essential for the catalytic activity of all omptins, including Pla. Why omptins require LPS for enzymatic activity is unknown. Here, we report the co-crystal structure of LPS-free Pla in complex with the activation loop peptide of human plasminogen, its natural substrate. The structure shows that in the absence of LPS, the peptide substrate binds deep within the active site groove and displaces the nucleophilic water molecule, providing an explanation for the dependence of omptins on LPS for enzymatic activity.

Structural basis for activation of an integral membrane protease by lipopolysaccharide., Eren E, van den Berg B, J Biol Chem. 2012 Jul 6;287(28):23971-6. Epub 2012 May 29. PMID:22645135

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[PLMN_HUMAN] Defects in PLG are the cause of plasminogen deficiency (PLGD) [MIM:217090]. PLGD is characterized by decreased serum plasminogen activity. Two forms of the disorder are distinguished: type 1 deficiency is additionally characterized by decreased plasminogen antigen levels and clinical symptoms, whereas type 2 deficiency, also known as dysplasminogenemia, is characterized by normal, or slightly reduced antigen levels, and absence of clinical manifestations. Plasminogen deficiency type 1 results in markedly impaired extracellular fibrinolysis and chronic mucosal pseudomembranous lesions due to subepithelial fibrin deposition and inflammation. The most common clinical manifestation of type 1 deficiency is ligneous conjunctivitis in which pseudomembranes formation on the palpebral surfaces of the eye progresses to white, yellow-white, or red thick masses with a wood-like consistency that replace the normal mucosa.[1][2][3][4][5][6][7][8]

Function

[COLY_YERPE] Seems to play an essential role in plague transmission by mediating flea blockage in a temperature-dependent fashion. Fibrinolytic activity prevails at 37 degrees Celsius whereas coagulase expression predominates at lower temperatures (<30 degrees Celsius). Activates plasminogen by cleaving it. [PLMN_HUMAN] Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells.[9] Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo.[10]

About this Structure

4dcb is a 2 chain structure with sequence from Yersinia pestis. Full crystallographic information is available from OCA.

Reference

  • Eren E, van den Berg B. Structural basis for activation of an integral membrane protease by lipopolysaccharide. J Biol Chem. 2012 Jul 6;287(28):23971-6. Epub 2012 May 29. PMID:22645135 doi:10.1074/jbc.M112.376418
  1. Ichinose A, Espling ES, Takamatsu J, Saito H, Shinmyozu K, Maruyama I, Petersen TE, Davie EW. Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):115-9. PMID:1986355
  2. Azuma H, Uno Y, Shigekiyo T, Saito S. Congenital plasminogen deficiency caused by a Ser572 to Pro mutation. Blood. 1993 Jul 15;82(2):475-80. PMID:8392398
  3. Miyata T, Iwanaga S, Sakata Y, Aoki N. Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6132-6. PMID:6216475
  4. Miyata T, Iwanaga S, Sakata Y, Aoki N, Takamatsu J, Kamiya T. Plasminogens Tochigi II and Nagoya: two additional molecular defects with Ala-600----Thr replacement found in plasmin light chain variants. J Biochem. 1984 Aug;96(2):277-87. PMID:6238949
  5. Kikuchi S, Yamanouchi Y, Li L, Kobayashi K, Ijima H, Miyazaki R, Tsuchiya S, Hamaguchi H. Plasminogen with type-I mutation is polymorphic in the Japanese population. Hum Genet. 1992 Sep-Oct;90(1-2):7-11. PMID:1427790
  6. Schuster V, Mingers AM, Seidenspinner S, Nussgens Z, Pukrop T, Kreth HW. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood. 1997 Aug 1;90(3):958-66. PMID:9242524
  7. Higuchi Y, Furihata K, Ueno I, Ishikawa S, Okumura N, Tozuka M, Sakurai N. Plasminogen Kanagawa-I, a novel missense mutation, is caused by the amino acid substitution G732R. Br J Haematol. 1998 Dec;103(3):867-70. PMID:9858247
  8. Schuster V, Seidenspinner S, Zeitler P, Escher C, Pleyer U, Bernauer W, Stiehm ER, Isenberg S, Seregard S, Olsson T, Mingers AM, Schambeck C, Kreth HW. Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood. 1999 May 15;93(10):3457-66. PMID:10233898
  9. Rossignol P, Ho-Tin-Noe B, Vranckx R, Bouton MC, Meilhac O, Lijnen HR, Guillin MC, Michel JB, Angles-Cano E. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem. 2004 Mar 12;279(11):10346-56. Epub 2003 Dec 29. PMID:14699093 doi:10.1074/jbc.M310964200
  10. Rossignol P, Ho-Tin-Noe B, Vranckx R, Bouton MC, Meilhac O, Lijnen HR, Guillin MC, Michel JB, Angles-Cano E. Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells. J Biol Chem. 2004 Mar 12;279(11):10346-56. Epub 2003 Dec 29. PMID:14699093 doi:10.1074/jbc.M310964200

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