Structural Requirements for Major Histocompatibility Complex Class II Invariant Chain Endocytosis and Lysosomal Targeting

The invariant chain (Ii) targets newly synthesized major histocompatibility complex class II complexes to a lysosome-like compartment. Previously, we demonstrated that both the cytoplasmic tail (CT) and transmembrane (TM) domains of Ii were sufficient for this targeting and that the CT contains two...

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Bibliographic Details
Published in:The Journal of biological chemistry 1998-08, Vol.273 (32), p.20644-20652
Main Authors: Kang, Sunghyun, Liang, Liang, Parker, Cynthia D., Collawn, James F.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Ammonium Chloride - pharmacology
Animals
Antigens, Differentiation, B-Lymphocyte - chemistry
Chick Embryo
Endocytosis - physiology
Histocompatibility Antigens Class II - chemistry
Humans
Kinetics
Lysosomes - physiology
Membrane Proteins - chemistry
Molecular Sequence Data
Mutation - genetics
Receptors, Transferrin - chemistry
Recombinant Fusion Proteins - chemistry
Structure-Activity Relationship
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Summary:The invariant chain (Ii) targets newly synthesized major histocompatibility complex class II complexes to a lysosome-like compartment. Previously, we demonstrated that both the cytoplasmic tail (CT) and transmembrane (TM) domains of Ii were sufficient for this targeting and that the CT contains two di-leucine signals, 3DQRDLI8 and12EQLPML17 (Odorizzi, C. G., Trowbridge, I. S., Xue, L., Hopkins, C. R., Davis, C. D., and Collawn, J. F. (1994) J. Cell Biol. 126, 317–330). In the present study, we examined the relationship between signals required for endocytosis and those required for lysosomal targeting by analyzing Ii-transferrin receptor chimeras in quantitative transport assays. Analysis of the Ii CT signals indicates that although3DQRDLI8 is necessary and sufficient for endocytosis, either di-leucine signal is sufficient for lysosomal targeting. Deletions between the two signals reduced endocytosis without affecting lysosomal targeting. Transplantation of the DQRDLI sequence in place of the EQLPML signal produced a chimera that trafficked normally, suggesting that this di-leucine sequence coded for an independent structural motif. Structure-function analysis of the Ii TM region showed that when Ii TM residues 11–19 and 20–29 were individually substituted for the corresponding regions in the wild-type transferrin receptor, lysosomal targeting was dramatically enhanced, whereas endocytosis remained unchanged. Our results therefore demonstrate that the structural requirements for Ii endocytosis and lysosomal targeting are different.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.273.32.20644