Abstract
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 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 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.
Highlights
The structure of the cell surface protein CD44, from its N-terminus to its C-terminus, consists of a globular hyaluronan binding domain (HABD), a stalk domain, a single-pass transmembrane domain, and a cytoplasmic domain [1, 2]
The already-complex structural biology of CD44 is further complicated by variable splicing of the RNA transcript of the CD44 gene, which yields a variety of different patterns of amino acid insertion into the stalk domain and which modulates CD44 function [1, 13, 14], and by shedding that produces soluble CD44 [15]
The first is that the Tyr42 backbone dihedral angle φ can act as a molecular switch to convert the HABD HA-binding site from the open A state to the closed B state, which includes the formation of direct contact between HA and the Arg41 sidechain [62]
Summary
University of Minnesota, USA Ichio Shimada, The University of Tokyo, Japan. Specialty section: This article was submitted to Inflammation, a section of the journal
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