J Cell Physiol. 2010 Feb;222(2):328-35. doi: 10.1002/jcp.21956.

Functional multimerization of mucolipin channel proteins.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Curcio-Morelli, C., Zhang, P., Venugopal, B., Charles, F. A., Browning, M. F., Cantiello, H. F., Slaugenhaupt, S. A.,
["Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA."]
MCOLN1 encodes mucolipin-1 (TRPML1), a member of the transient receptor potential TRPML subfamily of channel proteins. Mutations in MCOLN1 cause mucolipidosis-type IV (MLIV), a lysosomal storage disorder characterized by severe neurologic, ophthalmologic, and gastrointestinal abnormalities. Along with TRPML1, there are two other TRPML family members, mucolipin-2 (TRPML2) and mucolipin-3 (TRPML3). In this study, we used immunocytochemical analysis to determine that TRPML1, TRPML2, and TRPML3 co-localize in cells. The multimerization of TRPML proteins was confirmed by co-immunoprecipitation and Western blot analysis, which demonstrated that TRPML1 homo-multimerizes as well as hetero-multimerizes with TRPML2 and TRPML3. MLIV-causing mutants of TRPML1 also interacted with wild-type TRPML1. Lipid bilayer re-constitution of in vitro translated TRPML2 and TRPML3 confirmed their cation channel properties with lower single channel conductance and higher partial permeability to anions as compared to TRPML1. We further analyzed the electrophysiological properties of single channel TRPML hetero-multimers, which displayed functional differences when compared to individual TRPMLs. Our data shows for the first time that TRPMLs form distinct functional channel complexes. Homo- and hetero-multimerization of TRPMLs may modulate channel function and biophysical properties, thereby increasing TRPML functional diversity.
PMID: 19885840External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML2 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML2 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML3 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML3 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
TRPML2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
TRPML3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Functional consequence Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
TRP channel Interactor Method Post-translational modification Subcellular trafficking Activity Reference
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML2 Patch clamp New channel creation 19885840
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML3 Patch clamp New channel creation 19885840
TRPML2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Patch clamp New channel creation 19885840
TRPML3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Patch clamp New channel creation 19885840
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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