Mammalian StAR-related lipid transfer (START) domains with specificity for cholesterol: structural conservation and mechanism of reversible binding.
The StAR-related lipid transfer (START) domain is an evolutionary conserved protein module of approximately 210 amino acids. There are 15 mammalian proteins that possess a START domain. Whereas the functions and specific ligands are being elucidated, 5 of them have already been shown to bind specifically cholesterol. The most intensively studied member of this subclass is the steroidogenic acute regulatory protein (StAR) or STARD1. While its role in steroid hormone production has been demonstrated, much less is understood about how its START domain specifically recognizes cholesterol and how it releases it to be transferred inside the mitochondria of steroidogenic cell of the gonads and adrenal cortex. A major obstacle that is slowing down progress in this area is the lack of knowledge of the 3D structures of the START domain of StAR in both its free and complexed forms. However, 3D models of the START domain of StAR and mechanisms of binding have been proposed. In addition biophysical studies aimed at validating the models and mechanism have been published. What's more, the crystal structures of the free forms of 3 START domains (STARD3, STARD4 and STARD5) known to specifically bind cholesterol have been elucidated so far. In this chapter, we will review and critically summarize existing data in order to provide the most current view and status of our understanding of the structure and reversible cholesterol binding mechanism of START domains.
Lavigne
Pierre
P
Département de Pharmacologie, Institut de Pharmacologie, Université de Sherbrooke, Sherbrooke, QC, Canada. Pierre.lavigne@usherbrooke.ca
Najmanivich
Rafael
R
Lehoux
Jean-Guy
JG
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D026901:Membrane Transport Proteins / Q000502:physiology; D008956:Models, Chemical; D008958:Models, Molecular; D010750:Phosphoproteins / Q000502:physiology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D000098682:Steroidogenic Acute Regulatory Protein
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; C105684:STARD3 protein, human; C456544:STARD4 protein, human; C456546:STARD5 protein, human; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol