Novel C-terminally truncated isoforms of the CXC chemokine beta-thromboglobulin and their impact on neutrophil functions.
The neutrophil agonist neutrophil-activating peptide-2 (NAP-2) arises through proteolytic processing of platelet-derived N-terminally extended inactive precursors, the most abundant one being connective tissue-activating peptide-III (CTAP-III). Apart from N-terminal processing, C-terminal processing also appears to participate in the functional regulation of NAP-2, as indicated by our recent identification of an isoform missing four C-terminal amino acids, NAP-2 (1-66), which was about threefold more potent than full-size NAP-2. In the present study, we report on the discovery and identification of natural NAP-2 (1-63), an isoform truncated by seven C-terminal residues. Functional and receptor-binding analyses demonstrated that NAP-2 (1-63) represents the most active isoform, being about fivefold more potent than full-size NAP-2. Analyses of rNAP-2 isoforms successively truncated at the C terminus by up to eight residues suggest functionally important roles for acidic residues and for the leucine at position 63, a residue highly conserved within CXC chemokines. Finally, we report on a novel C-terminally truncated isoform of CTAP-III (CTAP-III (1-81)) representing the potential precursor of NAP-2 (1-66). We show that C-terminal truncation in CTAP-III enhances its potency to desensitize chemokine-induced neutrophil activation, indicating that C-terminal processing might not only serve to enhance neutrophil activation, but might as well participate in the down-regulation of an inflammatory response.
Ehlert
J E
JE
Department of Immunology and Cell Biology, Forschungszentrum Borstel, Germany. jehlert@fzborstel.de
Gerdes
J
J
Flad
H D
HD
Brandt
E
E
D001779:Blood Coagulation Factors / Q000378:metabolism; D019743:Chemokines, CXC / Q000737:chemistry*; D003594:Cytoplasmic Granules / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D001620:beta-Thromboglobulin / Q000737:chemistry / Q000378:metabolism*
D001779:Blood Coagulation Factors; D019743:Chemokines, CXC; C061615:PPBP protein, human; D010455:Peptides; D020033:Protein Isoforms; D011498:Protein Precursors; D001620:beta-Thromboglobulin; C009862:connective tissue-activating peptide; C018329:low affinity platelet factor 4