Specific cleavage of the alpha 4 integrin associated with activation of peripheral T lymphocytes.
The heterodimeric VLA-4 integrin has been implicated in lymphocyte migration to inflamed peripheral tissues, lympho-haemopoiesis and autoimmune disease. To determine the structure and function of VLA-4 in physiological processes, molecular forms of the VLA-4 alpha-chain were analysed during T-cell activation. The results showed that prolonged activation of human peripheral T cells was associated with increased cleavage of the 150,000 MW alpha 4 chain into 80,000 and 66,000 MW fragments. Similar-sized alpha 4 fragments could also be generated from 150,000 MW alpha 4 on intact resting T cells by brief trypsinization, whereas trypsin treatment of isolated 150,000 MW alpha 4 resulted in nearly complete protein degradation. Native 80,000 and 66,000 MW alpha 4 chains on activated T cells could not be digested further by trypsin. These results indicated that specific cleavage of 150,000 MW alpha 4 was largely dependent on the tertiary structure of native alpha 4 chains. To determine the specific cleavage site in alpha 4 on peripheral T cells, VLA-4 was isolated and purified from in vitro-activated T cells and the N-terminus of the 66,000 MW fragment was partially sequenced. The sequence SKR/STE was identified as the specific alpha 4 cleavage site on T cells. These results indicate that T cells, upon activation, acquire an enhanced dipeptidase processing activity, which cleaves alpha 4 at a specific site.
Blue
M L
ML
Institute for Arthritis and Autoimmunity, Miles Research Center, West Haven, Connecticut 06516.
Davis
G
G
Conrad
P
P
Kelley
K
K
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D006801:Humans; D039001:Integrin alpha Chains; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016029:Receptors, Very Late Antigen / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014357:Trypsin
C063493:CDw49d; D039001:Integrin alpha Chains; D016029:Receptors, Very Late Antigen; D014357:Trypsin