Re-examining structural features of caveolins: 25 years later

Caveolae are flask-shaped signaling platforms in the plasma membrane of cells.They broadly participate in different types of cellular processes including signaling, lipid homeostasis, caveolaemediated endocytosis and pathogen invasion.The principal protein responsible for caveolae formation is the integral membrane protein, caveolin (caveolin-1, -2, -3).Caveolin oligomer assembly is believed to drive the membrane curvature that is a defining feature of caveolae.Capturing this phenomenon in biophysical studies has presented ongoing challenges for researchers over the past several decades.Much of what is reported about caveolin structure and oligomerization has resorted to isolating distinct regions of the protein for characterization.In this paper, major findings in the field of caveolae from the past several decades are summarized.Much of the discussion centers on caveolin-1, the most ubiquitous and minimal requirement for caveolae formation in non-muscle tissue.In the article, a comprehensive overview of what has been gleaned from cell biology and in vitro studies of caveolin is presented, summarizing both what we know and the challenges that remain.We attempt to reconcile structural features of caveolin and highlight unanswered questions, including but not limited to, the cytosolic disordered N-terminal region and its role in caveolin function.This work will help to illuminate new avenues for research in the field of caveolae, lipid rafts and disordered proteins.Important considerations about the challenges working with caveolin are conveyed in concert with a discussion about membrane proteins and the role of the membrane lipid bilayer on their structural conformation; followed by a critique of current approaches aimed at elucidating caveolin structure and oligomeric assembly.