Platelet receptor recognition domain on the. gamma. chain of human fibrinogen and its synthetic peptide analogues
- Harvard Medical School, Boston, MA (USA)
The authors have shown previously that the domain recognizing receptors on activated human platelets is located on the human fibrinogen {gamma} chain between residues 400 and 411. To study the correlation between the structure of this segment of the {gamma} chain and its reactivity toward receptors on ADP-activated human platelets, they designed a series of analogues containing replacements at 9 out of 12 positions. A double substitution of the normal His{sup 400}-His{sup 401} sequence by Ala-Ala reduced the inhibitory potency of the dodecapeptide 3-fold. When Lys{sup 406} was replaced by Arg, the inhibitory potency of the dodecapeptide decreased 15 times. On the other hand, substitution of Ala{sup 408} with Arg increased the inhibitory potency of the dodecapeptide 6-fold. A drastic decrease in the reactivity of the dodecapeptide toward platelet receptors was observed when Val{sup 411} was replaced by leucine or cysteine or tyrosine. A 3-fold decrease in reactivity was noted when Val{sup 411} was substituted with phenylalanine. Amidation of the carboxy-terminal Val{sup 411} also produced a significant decrease in dodecapeptide reactivity. With seven residues (His{sup 400}, His{sup 401}, Leu{sup 402}, Lys{sup 406}, Gln{sup 407}, Asp{sup 410}, and Val{sup 411}) preserved, substitution of the intervening five amino acids with nonpolar leucine or polar serine, increasing or decreasing the hydrophobicity of the dodecapeptide, reduced more than 16-fold its inhibitory potency. Rabbit antibody Fab fragments directed against the human fibrinogen {gamma}-chain peptide encompassing residues 385-411 inhibited 50% of {sup 125}-fibrinogen binding at a 2:1 stoichiometry with regard to {sup 125}I-fibrinogen. In vivo infusion of dodecapeptide with a native sequence into rabbit mesenteric artery caused reversible inhibition of hemostatic platelet thrombus formation.
- OSTI ID:
- 5547183
- Journal Information:
- Biochemistry; (USA), Journal Name: Biochemistry; (USA) Vol. 28:7; ISSN 0006-2960; ISSN BICHA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
AMINO ACID SEQUENCE
AMINO ACIDS
AZOLES
BETA DECAY RADIOISOTOPES
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD COAGULATION FACTORS
BLOOD PLATELETS
BODY FLUIDS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
COAGULANTS
CROSS-LINKING
DAYS LIVING RADIOISOTOPES
DOSE-RESPONSE RELATIONSHIPS
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
FIBRINOGEN
GLOBULINS
GLUTAMIC ACID
HEMATOLOGIC AGENTS
HEMOSTATICS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HISTIDINE
IMIDAZOLES
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE ISOTOPES
ISOTOPES
LEUCINE
LYSINE
MATERIALS
MEMBRANE PROTEINS
MOLECULAR STRUCTURE
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PEPTIDES
POLYMERIZATION
PROTEINS
RADIOISOTOPES
RECEPTORS
STOICHIOMETRY
VALINE