Revealing the mechanisms of protein disorder and N-glycosylation in CD44-hyaluronan binding using molecular simulation

Revealing the mechanisms of protein disorder and N-glycosylation in CD44-hyaluronan binding using molecular simulation

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The extracellular N-terminal hyaluronan binding domain (HABD) of CD44 is a small globular domain that confers hyaluronan (HA) binding functionality to this large transmembrane glycoprotein.When recombinantly expressed by itself, HABD exists as a globular water-soluble protein that retains the capacity to bind HA.This has enabled atomic-resolution structural biology experiments that have revealed the structure of HABD and its binding mode with oligomeric HA.Such experiments have also pointed to an order-to-disorder transition in HABD that is associated with HA binding.However, it had remained unclear how this iphone xr price calgary structural transition was involved in binding since it occurs in a region of HABD distant from the HA-binding site.

Furthermore, HABD is known to be N-glycosylated, and such glycosylation can diminish HA binding when the associated N-glycans are capped with sialic acid residues.The intrinsic flexibility of disordered proteins and of N-glycans makes it difficult to apply experimental structural biology approaches to probe the molecular mechanisms of how the order-to-disorder transition and N-glycosylation majicontrast red can modulate HA binding by HABD.We review recent results from molecular dynamics simulations that provide atomic-resolution mechanistic understanding of such modulation to help bridge gaps between existing experimental binding and structural biology data.Findings from these simulations include: Tyr42 may function as a molecular switch that converts the HA binding site from a low affinity to a high affinity state; in the partially-disordered form of HABD, basic amino acids in the C-terminal region can gain sufficient mobility to form direct contacts with bound HA to further stabilize binding; and terminal sialic acids on covalently-attached N-glycans can form charge-paired hydrogen bonding interactions with basic amino acids that could otherwise bind to HA, thereby blocking HA binding to glycosylated CD44 HABD.