Lipid Rafts' Failure to Launch

Debating what binds membrane microdomains

Jun 1, 2006
Jill U. Adams
<figcaption> Credit: THOM GRAVES MEDIA</figcaption>

Since the term was coined a decade ago, lipid rafts have turned out to be slippery characters. While conceptually appealing - picture a lipid platform recruiting key proteins to carry out membrane functions such as signaling or endocytosis - basic questions remain as to what really pulls proteins and lipids together in these membrane domains.

Now, in what biophysicist Anne Kenworthy of Vanderbilt University calls "a big splashy paper," an outsider to the field rebuffs the idea that lipids drive the coalescence of membrane components (as in model 1). Using single-molecule fluorescence imaging to follow proteins in the membrane, Ronald Vale at the University of California, San Francisco, showed that protein-protein interactions are the major force responsible for localization at T-cell receptor (TCR) signaling domains.1

Protein-Protein or Lipid-Protein

Better known for his work on molecular motors, Vale broke into lipid rafts and T cells looking for open questions in cell biology that might benefit from his live-cell microscopy method.

Vale watched the movement of TCR signaling proteins - the tyrosine kinase Lck and the adaptor protein LAT - by labeling them with fluorophores. Movies he created show these proteins being momentarily trapped by clusters of proteins, more so after receptor activation. Mutations that rendered some proteins unable to associate with lipid rafts did not prevent them from gathering at the signaling domains, but mutations that precluded protein-protein interaction did (as in model 2).

Critics counter that Vale came to the party too late: Looking ten minutes after T-cell stimulation (as Vale did) may miss lipid-protein interactions. Barbara Baird of Cornell University says lipids play a more prominent role early on, initiating "structural rearrangements that enable the proteins to connect." Once the complex builds up, "then I think it does become protein dominated."

Protein-interaction dynamics, in turn, are influenced by their lipid environment, says Thomas Harder of Oxford University. In rafts, lipids are packed more tightly and may promote longer protein-protein interactions. Equally important is the exclusion of certain proteins from rafts. For example, in T cells the ordered lipids surrounding the TCR seem to favor kinases over phosphatases, Harder says, tipping the balance between opposing pathways.

Vale allows that if lipid rafts are as small and transient as some researchers suppose, his methods may not yet detect them. Moreover, interplay between both forces isn't out of the question. Still, he says, lipids have been overemphasized since rafts were first proposed. "What we found is a very pronounced and dominant organization of membrane domains that look to be primarily based on protein-protein interactions."

1. A.D. Douglass, R.D. Vale, "Single- microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells," Cell, 121:937-50, 2005.