J Cell Physiol. 2010 Feb;222(2):328-35.

Functional multimerization of mucolipin channel proteins.External

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
Arrow2 Screening Arrow2 Validation: In vitro validation Arrow2 Validation: In vivo validation Arrow2 Characterization Arrow2 Functional consequence Arrow2 top
Validation: In vivo validation Toggle
  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 TRPML2 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML1 Link TRPML2 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
TRPML1 Link TRPML3 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML1 Link TRPML3 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
TRPML2 Link TRPML1 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML2 Link TRPML1 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
TRPML3 Link TRPML1 Co-immunofluorescence staining CHO Human Full-length Human Full-length 19885840
TRPML3 Link TRPML1 Co-immunoprecipitation CHO Human Full-length Human Full-length 19885840
(Link: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Arrow2 Screening Arrow2 Validation: In vitro validation Arrow2 Validation: In vivo validation Arrow2 Characterization Arrow2 Functional consequence Arrow2 top
Functional consequence Toggle
TRP channel Interactor Method Post-translational modification Subcellular trafficking Activity Reference
TRPML1 Link TRPML2 Patch clamp New channel creation 19885840
TRPML1 Link TRPML3 Patch clamp New channel creation 19885840
TRPML2 Link TRPML1 Patch clamp New channel creation 19885840
TRPML3 Link TRPML1 Patch clamp New channel creation 19885840
(Link: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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