Pleckstrin homology domain-containing family M member 1 (PLEKHM1)

Pleckstrin homology domain-containing family M member 1 (PLEKHM1) is a multifunctional cytoplasmic adaptor protein that contains a pleckstrin homology (PH) domain and a RUN domain, as well as a C-terminal Rubicon Homology (RH) domain. It acts as a key effector in lysosomal trafficking, facilitating vesicle fusion with late endosomes and lysosomes by binding directly to small GTPases such as RAB7A and ARL8B[4][5]. PLEKHM1 is indispensible for bone homeostasis through its critical role in the positioning and secretion of lysosomes in osteoclasts, enabling proper bone resorption. Mutations in the PLEKHM1 gene are causative for human and rat osteopetrosis and lead to increased trabecular bone mass and defects in ruffled border formation due to aberrant lysosome trafficking[1][2][3][4]. PLEKHM1 forms complexes with DEF8, RAB7, FAM98A, and NDEL1 to link lysosomes to microtubules for transportation and secretion during bone remodeling[1][2]. Although no approved drugs currently target PLEKHM1, its critical function in osteoclast biology renders it a candidate therapeutic target for disorders characterized by excessive bone resorption, such as osteoporosis[2][4]. PLEKHM1 is not a receptor, enzyme, or transporter in the classical sense but functions as an adaptor protein in cytoplasmic vesicle trafficking. Interference with PLEKHM1 interactions—particularly with RAB7—offers a potential therapeutic avenue for bone metabolic diseases by blocking excessive bone resorption[2][4]. PLEKHM1 is under active investigation for its molecular mechanisms and therapeutic utility, especially regarding its critical domains required for interaction with RAB7 and its indispensable role in skeletal biology[2][4][5].

Other names

AP162B2OPTA3OPTB6KIAA0356pleckstrin homology and RUN domain containing M1pleckstrin homology domain-containing family M member 1162 kDa adapter protein