Folding propensity of intrinsically disordered proteins by osmotic stress

Abstract

Proteins imparted with intrinsic disorder conduct a range of essential cellular functions. To better understand the folding and hydration properties of intrinsically disordered proteins (IDPs), we used osmotic stress to induce conformational changes in nuclear co-activator binding domain (NCBD) and activator for thyroid hormone and retinoid receptor (ACTR) separate from their mutual binding. Osmotic stress was applied by the addition of small and polymeric osmolytes, where we discovered that water contributions to NCBD folding always exceeded those for ACTR. Both NCBD and ACTR were found to gain α-helical structure with increasing osmotic stress, consistent with their folding upon NCBD/ACTR complex formation. Using small-angle neutron scattering (SANS), we further characterized NCBD structural changes with the osmolyte ethylene glycol. Here a large reduction in overall size initially occurred before substantial secondary structural change. By focusing on folding propensity, and linked hydration changes, we uncover new insights that may be important for how IDP folding contributes to binding.

Metabolic Profile of Oral Squamous Carcinoma Cell Lines Relies on a Higher Demand of Lipid Metabolism in Metastatic Cells

“…These are compounds that interchangeably stabilize the intracellular milieu by buffering osmotic perturbations, for instance. The notion that the osmolytes and compatible solutes listed in Table 1 may play such a role opens up the possibility that they could act as effectors of a much broader regulatory network, given their ability to affect flexible and random coil conformations of transcription factors ( 41 – 43 ). In this way, the compounds detected in our metabolomic analyses may have a dual role.…”

NFAT5, which protects against hypertonicity, is activated by that stress via structuring of its intrinsically disordered domain

“…Hypertonic activation of NFAT5 also increases the expression of target genes that synthesize or transport multiple organic osmolytes (12). Certain organic osmolytes are known to act as chemical chaperones to fold/stabilize proteins including ID regions of many transcription factors (58)(59)(60)(61). NFAT5 contains multiple regions predicted to be ID, including its NTD and CTD, both important for NFAT5 function.…”

Does water stress promote the proteome-wide adjustment of intrinsically disordered proteins in plants?

“…IDRs in chaperones probably act not only as regulatory/structural components, but might also help them to perform their activity, without compromising their own structure by avoiding undesirable hydrophobic interactions, since attaching disordered regions to ordered proteins or aggregation-prone sequences helps to protect them from aggregation and thus making them more soluble (Minde et al 2013;Liu and Huang 2014). Some IDPs/IDPRs can undergo disorder-to-order transitions when their environment changes, such as during desiccation and osmotic stress (Goyal et al 2003;Shih et al 2010;Mansouri et al 2016) and perform activities other than when they are in their disordered state (Popova et al 2011).…”