START Domain Protein Structure and Ligand Specificity

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

“…5a). As observed for the binding of Cholesterol to STARD11213 and bile acids to STARD54653, the binding of testosterone to STARD6 is in the slow exchange regime (not shown). In agreement with CD measurements (Fig.…”

“…We show that this leads to the coalescence of the buried binding site with the surrounding bulk water molecules to allow for ligand entry. Despite their low primary structure homologies12, we propose that this conformational exchange and binding mechanism, presented here, will be conserved across the fifteen human START domains. In this regard, significant fluctuations (high B-factors) in the Ω 1 loop are conserved in the structure of the apo-forms of START domains in the majority of the crystal structures reported210111459.…”

“…Compared to classical cases of ligand binding, binding of sterol molecules (and other lipids) to START domains is complicated by the fact that the binding site is completely buried inside the α/β helix grip fold. As reviewed elsewhere1213, different conformational changes have been proposed to give access and allow for the exit of ligands but their time-scales and synchrony remains to be determined. These structural changes involve the opening of the Ω 1 loop, the C-terminal helix and concerted movements between the Ω 1 loop and the C-terminal (α 4 ) helix2 as well as between Ω 1 loop and α 3 helix1415.…”

Thirty-Eight-Year Follow-Up of Two Sibling Lipoid Congenital Adrenal Hyperplasia Patients Due to Homozygous Steroidogenic Acute Regulatory (STARD1) Protein Mutation. Molecular Structure and Modeling of the STARD1 L275P Mutation

“…It was first proposed that STARD1 acts as a cholesterol shuttle for transferring cholesterol to the IMM via a hydrophobic tunnel revealed by the crystal structure of MLN64-START (Tsujishita and Hurley, 2000), but the exact mechanism by which STARD1 releases cholesterol to the IMM is unknown (Stocco, 2001). According to computer homology models based on MLN64 structure, STARD1 does not contain a tunnel, but a hydrophobic pocket that can accommodate one molecule of cholesterol (Mathieu et al, 2002a,b; Baker et al, 2005; Yaworsky et al, 2005; Murcia et al, 2006; Lavigne et al, 2010; Thorsell et al, 2011; Létourneau et al, 2014, 2015); the STARD1 crystal structure corroborates this hydrophobic pocket. Several mutations that result in LCAH were mapped onto the MLN64-START structure, in positions residing within the hydrophobic tunnel; these mutations would destabilize the tunnel.…”