Page 20 - Hormel Report 2021

Rhoderick Brown, Ph.D.
“Unraveling how sphingolipid transfer proteins help regulate inflammation and programmed cell death is of fundamental importance
for developing new therapeutic approaches
to treat diseases such as cancer that often
develop chemoresistance to evade normal
programmed cell death processes.”
Rhoderick “Rick” Brown
20 | THE HORMEL INSTITUTE // Membrane Biochemistry and
Molecular Biophysics
SECTION LEADER / PROFESSOR
UNIVERSITY OF MINNESOTA
Our research focuses on proteins that interact transiently with membrane lipids. Such proteins include lipid transfer
proteins that shuttle sphingolipids between intracellular membranes to help form and maintain ‘raft’ microdomains present in certain organelles. Other proteins include modular lipid- binding domains (e.g. C2-domains) that act as membrane targeting and anchoring devices for select proteins that translocate to membranes to function. Cloning of glyco(sphingo)lipid transfer proteins (GLTPs) from mammals, plants and fungi enabled determination of their apo and holo molecular structures by X ray crystallography. A unique protein fold (GLTP-fold) emerged that rec- ognizes and binds glycolipids to facilitate their in- termembrane transfer. We also have deciphered how: i) different glycolipids are accommodated within the glycolipid binding site; ii) the function played by tryptophans in glycolipid binding and membrane interaction; iii) the structural basis
for more focused glycolipid selectivity by fungal GLTP and the human FAPP2-GLTPH
domain. Our findings are published in
Nature, eLife, PLoS Biology, Structure, The Journal of Biological Chemistry, Biophysical Journal, Biochemistry, and Journal of Lipid Research.
We also discovered new GLTP superfamily members, ceramide-1- phosphate (C1P) transfer proteins (CPTPs). In Nature, we reported structural characterization of human CPTP, its intracellular location in
mammalian cells, and showed that CPTP deple- tion by RNAi leads to C1P over-accumulation
in the trans-Golgi. The C1P over-accumulation triggers cytoplasmic phospholipase A2 (cPLA2α) action that releases arachidonic acid used
for downstream pro inflammatory eicosanoid production. In eLife, we recently reported the selection mechanism used by the cPLA2α C2-domain to target membranes rich in phos- phatidylcholines. The insights could help develop new treatments for sepsis and other inflamma- tion-associated pathologic conditions, i.e. cancer, diabetes, dementia.