Genetic and structural studies of RABL3 reveal an essential role in lymphoid development and function

Xue Zhong, Lijing Su, Yi Yang, Evan Nair-Gill, Miao Tang, Priscilla Anderton, Xiaohong Li, Jianhui Wang, Xiaoming Zhan, Diana R. Tomchick, Chad A. Brautigam, Eva Marie Y. Moresco, Jin Huk Choi, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


The small GTPase RABL3 is an oncogene of unknown physiological function. Homozygous knockout alleles of mouse Rabl3 were embryonic lethal, but a viable hypomorphic allele (xiamen [xm]) causing in-frame deletion of four amino acids from the interswitch region resulted in profound defects in lymphopoiesis. Impaired lymphoid progenitor development led to deficiencies of B cells, T cells, and natural killer (NK) cells in Rabl3xm/xm mice. T cells and NK cells exhibited impaired cytolytic activity, and mice infected with mouse cytomegalovirus (MCMV) displayed elevated titers in the spleen. Myeloid cells were normal in number and function. Biophysical and crystallographic studies demonstrated that RABL3 formed a homodimer in solution via interactions between the effector binding surfaces on each subunit; monomers adopted a typical small G protein fold. RABL3xm displayed a large compensatory alteration in switch I, which adopted a β-strand configuration normally provided by the deleted interswitch residues, thereby permitting homodimer formation. Dysregulated effector binding due to conformational changes in the switch I-interswitch-switch II module likely underlies the xm phenotype. One such effector may be GPR89, putatively an ion channel or G protein-coupled receptor (GPCR).

Original languageEnglish (US)
Pages (from-to)8563-8572
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number15
StatePublished - Apr 14 2020


  • GPR89
  • Lymphopoiesis
  • Small GTPase
  • X-ray crystallography

ASJC Scopus subject areas

  • General


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