Ragulator complex protein LAMTOR2

LAMTOR2 (Ragulator complex protein) is a 125-amino-acid scaffold protein that functions as a guanine nucleotide exchange factor (GEF) and membrane adapter within the Ragulator complex (UniProt: Q9Y2Q5). It mediates amino acid sensing and activation of mTORC1 signaling by recruiting and activating Rag GTPases to lysosomal membranes, thereby promoting cell growth in response to amino acids, growth factors, and energy status. The protein also enhances MAP kinase cascade efficiency through MAPK2 activation.

LAMTOR2 is expressed broadly in human tissues and is associated with immunodeficiency due to MAPBP-interacting protein defects (MIM 610798), which presents with congenital neutropenia, partial albinism, short stature, and immune cell deficiency (UniProt: Q9Y2Q5). Beyond this monogenic form, the Ragulator complex participates in fundamental nutrient-sensing pathways relevant to cellular homeostasis.

In Alzheimer's disease, LAMTOR2 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.36 across the analyzed subcellular fractions. This reduction may reflect impaired amino acid sensing and mTORC1 signaling dysregulation in the AD brain, potentially contributing to neuronal metabolic dysfunction.