Download PDF
Thromb Haemost 1994; 72(06): 869-873
DOI: 10.1055/s-0038-1648976
Original Article
Schattauer GmbH Stuttgart

Possible Structural Implications of 20 Mutations in the Protein C Protease Domain

Judith S Greengard
The Departments of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
,
John H Griffin
The Departments of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
,
Cindy L Fisher
The Departments of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
› Author Affiliations
Further Information

Publication History

Received 30 May 1994

Accepted after revision 08 August 1994

Publication Date:
06 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Analysis of naturally occurring protein mutations yields valuable insights into functionally important sequences. Characterizing mutations responsible for protein C deficiency at the molecular level has been the subject of intensive investigation. In a previous study, a three-dimensional model of the serine protease domain of protein C was used to analyze the set of protease domain mutations previously available. The mutations were largely found to fall into a limited number of categories. A recently updated protein C mutation data base has provided a number of new mutations which have been analyzed for structural predictions.

 

  • References

  • 1 Rezaie AR, Esmon NL, Esmon CT. The high affinity calcium-binding site involved in protein C activation is outside the first epidermal growth factor homology domain. J Biol Chem 1992; 267: 11701-11704
    PubMedGoogle Scholar
  • 2 Rezaie AR, Esmon CT. The function of calcium in protein C activation by thrombin and the thrombin-thrombomodulin complex can be distinguished by mutational analysis of protein C derivatives. J Biol Chem 1992; 267: 26104-26109
    PubMedGoogle Scholar
  • 3 Rezaie AR, Mather R, Sussman F, Esmon CT. Mutation of Glu-80 → Lys results in a protein C mutant that no longer requires Ca2+ for rapid activation by the thrombin-thrombomodulin complex. J Biol Chem 1994; 269: 3151-3154
    PubMedGoogle Scholar
  • 4 Rezaie AR, Esmon CT. Conversion of glutamic acid 192 to glutamine in activated protein C changes the substrate specificity and increases reactivity toward macromolecular inhibitors. J Biol Chem 1993; 268: 19943-19948
    PubMedGoogle Scholar
  • 5 Ehrlich HJ, Jaskunas R, Grinnell BW, Yan SB, Bang NU. Direct expression of recombinant activated human protein C, a serine protease. J Biol Chem 1989; 264: 14298-14304
    PubMedGoogle Scholar
  • 6 Yan SCB, Pazzano P, Chao YB, Walls JD, Berg DT, McClure DB, Grinnell BW. Characterization and novel purification of recombinant human protein C from three mammalian cell lines. Bio/Technology 1990; 8: 655-661
    CrossrefPubMedGoogle Scholar
  • 7 McClure DB, Walls JD, Grinnell BW. Post-translational processing events in the secretion pathway of human protein C, a complex vitamin K-depend-ent antithrombotic factor. J Biol Chem 1992; 267: 19710-19717
    PubMedGoogle Scholar
  • 8 Zhang L, Castellino FJ. Role of the hexapeptide disulfide loop present in the gamma-carboxyglutamic acid domain of human protein C in its activation properties and in the in vitro anticoagulant activity of activated protein C. Biochemistry 1991; 30: 6696-6704
    CrossrefPubMedGoogle Scholar
  • 9 Zhang L, Castellino FJ. A gamma-carboxyglutamic acid variant (gamma6D gamma7D) of human activated protein C displays greatly reduced activity as an anticoagulant. Biochemistry 1990; 29: 10828-10834
    CrossrefPubMedGoogle Scholar
  • 10 Zhang L, Jhingan A, Castellino FJ. Role of individual gamma-carboxyglutamic acid residues of activated human protein C in defining its in vitro anticoagulant activity. Blood 1992; 80 (04) 942-952
    PubMedGoogle Scholar
  • 11 Fisher CL, Greengard JS, Griffin JH. Models of the serine protease domain of the human antithrombotic plasma factor activated protein C and its zymogen. Protein Science 1994; 3: 588-599
    PubMedGoogle Scholar
  • 12 Wacey AI, Pemberton S, Cooper DN, Kakkar VV, Tuddenham EGD. A molecular model of the serine protease domain of activated protein C: Application to the study of missense mutations causing protein C deficiency. Br J Haematol 1993; 84: 290-300
    CrossrefPubMedGoogle Scholar
  • 13 Greengard JS, Fisher CL, Villoutreix B, Griffin JH. Structural basis for Type I and Type II deficiencies of antithrombotic plasma protein C: Patterns revealed by three-dimensional molecular modelling of mutations of the protease domain. Proteins 1994; 18: 367-380
    CrossrefPubMedGoogle Scholar
  • 14 Greer J. Comparative modeling methods: Application to the family of the mammalian serine proteases. Proteins 1990; 7: 317-334
    CrossrefPubMedGoogle Scholar
  • 15 Birktoft JJ, Blow DM. Structure of crystalline α-chymotrypsin (V). The atomic structure of tosyl-α-chymotrypsin at 2 Å resolution. J Mol Biol 1972; 68: 187-240
    CrossrefPubMedGoogle Scholar
  • 16 Witt I, Seydewitz HH, Asbeck D, Beck S, Nabel C. Protein C mutations in 10 unrelated families with symptomatic protein C deficiency. Ann Hematol 1994; 68 Suppl (Suppl. 02) A58
    PubMedGoogle Scholar
  • 17 Doig RG, Begley CG, McGrath KA. Three previously undescribed mutations of the protein C gene in families with hereditary protein C deficiency. Thromb Haemost 1993; 69: 644
    PubMedGoogle Scholar
  • 18 Miyata Z, Zheng Y-Z, Sakata T, Tsushima N, Kato H. Three missense mutations in the protein C heavy chain causing type I and type II protein C deficiency. Thromb Haemost 1994; 71 (01) 32-37
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofsteenge J. The refined 1.9 Å crystal structure of human alpha-thrombin: Interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO J 1989; 8: 3467-3475
    PubMedGoogle Scholar
  • 20 Walter J, Steigemann W, Singh TP, Bartunik H, Bode W, Huber R. On the disordered activation domain in trypsinogen. Chemical labelling and low-temperature crystallography. Acta Crystallog, Sect B 1982; 38: 1462-1720
    PubMedGoogle Scholar
  • 21 Tsukada H, Blow DM. Structure of α-chymotrypsin refined at 1.68 Å resolution. J Mol Biol 1985; 184: 703-711
    CrossrefPubMedGoogle Scholar
  • 22 Wang D, Bode W, Huber R. Bovine chymotrypsinogen A. X-ray crystal structure analysis and refinement of a new crystal form at 1.8 Å resolution J Mol Biol 1985; 185: 595-624
    CrossrefPubMedGoogle Scholar
  • 23 Collawn JF, Kuhn LA, Liu L-FS, Tainer JA, Trowbridge IS. Transplanted LDL and mannose-6-phosphate receptor internalization signals promote high-efficiency endocytosis of the transferrin receptor. EMBO J 1991; 10: 3247-3253
    PubMedGoogle Scholar
  • 24 Murakawa M, Okamura T, Kamura T, Kuroiwa M, Harada M, Niho Y. A comparative study of partial primary structures of the catalytic region of mammalian protein C. Br J Haematol 1994; 86: 590-600
    CrossrefPubMedGoogle Scholar
  • 25 Prevelige Jr P, Fasman GD. Chou-Fasman prediction of the secondary structure of proteins. The Chou-Fasman-Prevelige algorithm. In: Prediction of Protein Structure and the Principles of Protein Conformation Fasman GD. ed Plenum Press; 1989. pp 391-416
  • 26 Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT, Cardin AD, Kisiel W. Structure of human des(l–45) factor Xa at 2.2 Å resolution. J Mol Biol 1993; 232: 947-966
    CrossrefPubMedGoogle Scholar
  • 27 Mesters RM, Heeb MJ, Griffin JH. Interactions and inhibition of blood coagulation factor Va involving residues 311–325 of activated protein C. Protein Science 1993; 2: 1482-1489
    CrossrefPubMedGoogle Scholar
  • 28 Miyata T, Aruga R, Umeyama H, Bezeaud A, Guillin MC, Iwanaga S. Prothrombin Salakta: Substitution of glutamic acid-466 by alanine reduces fibrinogen clotting activity and the esterase activity. Biochemistry 1992; 31: 7457-7462
    CrossrefPubMedGoogle Scholar
  • 29 Braun PJ, Hofsteenge J, Chang JY, Stone SR. Preparation and characterization of proteolyzed forms of human α-thrombin. Thromb Res 1988; 50: 273-283
    CrossrefPubMedGoogle Scholar
  • 30 Hofsteenge J, Braun PJ, Stone SR. Enzymatic properties of proteolytic derivatives of human α-thrombin. Biochemistry 1988; 27: 2144-2151
    CrossrefPubMedGoogle Scholar
  • 31 Stubbs MT, Bode W. A player of many parts: The spotlight falls on thrombin’s structure. Thromb Res 1993; 69: 1-58
    CrossrefPubMedGoogle Scholar
  • 32 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper DN. Protein C deficiency: A database of mutations, 1995 Update. Thrombos Haemostas 1995 (in press)
    PubMedGoogle Scholar