Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved peptide motif
Year: 2025
Type: article
Abstract: Inherited mutations in VPS35 and LRRK2 kinase lead to hyperphosphorylation of Rab GTPases. RH2 domain-containing proteins from the RILP homology family, such as RILPL1, are Rab effectors that recognize the LRRK2-phosphorylated switch 2 threonine of phospho-Rab8A and phospho-Rab10. Phospho-Rabs are also seen on lysosomal membranes in complex with RILPL1 and TMEM55B, a 284-residue lysosomal membrane protein lacking homology to known proteins. Here, we report crystal structures of the cytosolic region 80–166 of TMEM55B alone and in complex with a C-terminal RILPL1 peptide, which we define as the TMEM55B-binding motif (TBM). The RILPL1 TBM sits in a shallow groove across two tandem RING-like domains of TMEM55B, each forming a Zn 2+ -stabilized 40-residue β-sandwich. Co-immunoprecipitation and mass spectrometry studies indicate that TMEM55B forms complexes independently of phospho-Rabs with conserved TBMs found in JIP3, JIP4, OCRL, WDR81, and TBC1D9B. These studies suggest that TMEM55B acts as a central hub for adaptor recruitment on lysosomes.
Source: Structure
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Funders: U.S. Department of Energy, Michael J. Fox Foundation for Parkinson's Research, Science Foundation Ireland, National Institutes of Health, Office of Science, Medical Research Council, National Institute of General Medical Sciences, Biological and Environmental Research, Argonne National Laboratory, Brookhaven National Laboratory
Awards: G1021286281, G102163711, G107546177, G1285306620, G1313983767, G1664757510, G171842289, G1867732070, G2004402655, G2287611682, G241279073, G262962599, G2857925935, G3067052642, G3075337988, G3262563802, G357145406, G3728080647, G409777406, G4155925329, G4429385918, G498139845, G5535608740, G5607048534, G5765906131, G6158515048, G6476969910, G6848031779, G6918803902, G7103625430, G7463374569, G78868261, G8701900045, G9000051782, Center for Biomolecular Structure (CBMS), NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W4416827180