Inhibitory fragment from the p41 form of invariant chain can regulate activity of cysteine cathepsins in antigen presentation.
Cysteine cathepsins play an indispensable role in proteolytic processing of the major histocompatibility complex class II-associated invariant chain (Ii) and foreign antigens in a number of antigen presenting cells. Previously it was shown that a fragment of 64 residues present in the p41 form of the Ii (p41 fragment) selectively inhibits the endopeptidase cathepsin L, whereas the activity of cathepsin S remains unaffected. Comparison of structures indicated that the selectivity of interactions between cysteine cathepsins and the p41 fragment is far from being understood and requires further investigation. The p41 fragment has now been shown also to inhibit human cathepsins V, K, and F (also, presumably, O) and mouse cathepsin L with K(i) values in the low nanomolar range. These K(i) values are sufficiently low to ensure complex formation at physiological concentrations. In addition we have found that the p41 fragment can inhibit cathepsin S too. These findings suggest that regulation of the proteolytic activity of most of the cysteine cathepsins by the p41 fragment is an important and widespread control mechanism of antigen presentation.
Mihelic
Marko
M
Department of Biochemistry and Molecular and Structural Biology, J Stefan Institute, Ljubljana, Slovenia.
Dobersek
Andreja
A
Guncar
Gregor
G
Turk
Dusan
D
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; C045084:invariant chain; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S; C117627:CTSV protein, human