Abstract
Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly. The highest affinity interaction was with the 30-kDa (heparin-binding) FN fragment, which also showed the greatest colocalization in cells and accommodated both HSP90 and heparin in the complex. The strength of interaction with HSP90 was influenced by the inherent stability of the FN fragments, together with the type of motif, where HSP90 preferentially bound the type-I FN repeat over the type-II repeat. Exogenous extracellular HSP90 led to increased incorporation of both full-length and 70-kDa fragments of FN into fibrils. Together, our data suggested that HSP90 may regulate FN matrix assembly through its interaction with N-terminal FN fragments.
Highlights
The 90-kDa ATP-driven chaperone family protein, heat shock protein 90 (HSP90), is widely distributed in eukaryotes, and creates a proteostasis hub inside the cell [1,2,3,4]
The N-terminal domain is required for ATP binding and hydrolysis, while the M domain is the primary binding site of client proteins and the C-terminal domain mediates dimerization and co-chaperone interactions (Figure 1)
We previously reported the direct interaction of full-length fibronectin (FL-FN) with both full-length
Summary
The 90-kDa ATP-driven chaperone family protein, heat shock protein 90 (HSP90), is widely distributed in eukaryotes, and creates a proteostasis hub inside the cell [1,2,3,4]. HSP90 function is best characterized in the cytoplasm, it is clear that HSP90 is exported to the extracellular space where it functions in the regulation of the immune response and cellular processes like migration and invasion [3,20,21,22,23,24]. In this way, extracellular HSP90 (exHSP90) potentiates the aggressiveness of cancer by promoting cancer progression and metastasis [20]. Compared to the wide range of intracellular clients, fewer exHSP90 clients have been identified, but those that have been identified include a number of extracellular matrix-associated proteins like matrix metalloproteases (MMP2 and MMP9), tissue plasminogen
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