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Fig. 5 | Cell Communication and Signaling

Fig. 5

From: Intrinsically disordered proteins play diverse roles in cell signaling

Fig. 5

Adapted from Zhou et al. [39]

Alternative splicing and PTMs, localized in intrinsically disordered regions, direct differential CXCR4 signaling. Predicted disorder identified by PONDR-FIT is depicted on a heat map (lower left), with red and blue indicating predicted disorder and order, respectively. A crystal structure of the structured regions (28–303 residues, PDB ID: 3OE9) is shown as a blue ribbon. Alternative splicing regulates receptor function by generating three tissue-specific isoforms by replacing the first five residues at the disordered N-terminus with other sequences of varying length. Multiple PTMs regulate different aspects of CXCR4 function: sulfation of Y7, Y12, and Y21 modulates receptor-ligand binding and dimerization [300], and glycosylation of N11 plays a role in masking the coreceptor functional activity [301]. Likewise, phosphorylation of Y157 is required for activation of the Gi-independent JAK2/STAT3 pathway [302]. Consequently, combinations of C-terminal PTMs are associated with three different biological processes: phosphorylation of S339 in G protein-coupled receptor kinase 6 (GRK6) and possibly GRK2 phosphorylation (two residues from S346-S348 and S351-S352) lead to receptor-arrestin3 binding, G protein uncoupling, and subsequent receptor desensitization. In contrast, phosphorylation of GRK3 (at the same regions as GRK2, but probably different residues), and GRK6 (S330 and S339) result in arrestin2 recruitment and subsequent ERK1/2 activation [303]. In addition, protein kinase C (PKC) and GRK6 phosphorylation (S324 or S325, S330 respectively) initiate degradation modulated by ubiquitination of K327, K331, and K333 [303, 304].

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