Crystal Structure of β-Arrestin 2 in Complex with CXCR7 Phosphopeptide

Abstract

Highlights d The structure of b-arrestin 2 bound to CXCR7 phosphopeptide (C7pp) was solved d The C7pp-bound b-arrestin 2 shows small inter-domain rotation d The three C7pp phosphates bind with the positively charged residues on b-arrestin 2 d The phosphate-binding pocket around Arg148 recognizes the first phosphate of C7pp

Receptor-Arrestin Interactions: The GPCR Perspective

“…Third, the finger, lariat, middle, and C-loops undergo significant rearrangements. While the positions of the lariat and middle loops are similar in all reported receptor/arrestin complexes, the finger loop and C-loop adopt distinct conformations in different structures of "active" arrestins ( Figure 2) [34,35,44]. Notably, the finger loop of V2Rpp-arrestin-2 complex forms an unstructured region superimposable neither with that of rhodopsin-arrestin-1 nor with that of β1AR-arrestin-2.…”

“…The extent of this twist varies between different structures of "active" arrestins [33,34,43,44]. "Active" arrestin conformations fall into two groups, those with small (~8 • ; PDB: 4ZRG, arrestin-1 R175E [45]; 3UGU, p44 splice variant of arrestin-1 [46]; 6K3F, C7pp-bound arrestin-3 [44]) and large (~18 • , PDB: 5TV1, IP 6 -bound-arrestin-3 [27]; 4JQI, V 2 Rpp-bound arrestin-2 [47]; 4J2Q, arrestin-1 p44 [48]; 4ZWJ, rhodopsin-bound arrestin-1 [40]; 5W0P, rhodopsin-bound arrestin-1 [43]; 6UP7, NTS 1 R-bound arrestin-2 [34]) interdomain twists. Specific phosphorylation patterns, i.e., the number and spatial distribution of phosphates, have been suggested as a potential mechanism governing the extent of the interdomain twist [44], but this idea requires experimental testing.…”

“…"Active" arrestin conformations fall into two groups, those with small (~8 • ; PDB: 4ZRG, arrestin-1 R175E [45]; 3UGU, p44 splice variant of arrestin-1 [46]; 6K3F, C7pp-bound arrestin-3 [44]) and large (~18 • , PDB: 5TV1, IP 6 -bound-arrestin-3 [27]; 4JQI, V 2 Rpp-bound arrestin-2 [47]; 4J2Q, arrestin-1 p44 [48]; 4ZWJ, rhodopsin-bound arrestin-1 [40]; 5W0P, rhodopsin-bound arrestin-1 [43]; 6UP7, NTS 1 R-bound arrestin-2 [34]) interdomain twists. Specific phosphorylation patterns, i.e., the number and spatial distribution of phosphates, have been suggested as a potential mechanism governing the extent of the interdomain twist [44], but this idea requires experimental testing. In addition to the extent of the interdomain twist, the orientation of arrestin-2 relative to the 7TM bundle of the receptor in complex with M 2 R [33], β 1 AR [49], and NTS 1 R [34] shows a 7 • , 20 • , and 90 • difference, respectively, compared to the rhodopsin-arrestin-1 complex.…”

“…Second, the interaction between residues in the polar core is disrupted, as evidenced by the movement of D290 in the lariat loop away from R169, which is an essential contact stabilizing the basal conformation of arrestin-2 [34]. Disruption of the polar core upon activation is a shared phenomenon in the activation of all arrestin subtypes [27,33,34,40,43,44,[47][48][49]. Third, the finger, lariat, middle, and C-loops undergo significant rearrangements.…”

Functions of the CXCL12 Receptor ACKR3/CXCR7—What Has Been Perceived and What Has Been Overlooked

“…This assumption is primarily based on the demonstration that ligand-dependent activation of CXCR7 results in the recruitment of arrestin to the receptor protein, which is followed by endocytosis and the activation of signaling pathways (Rajagopal et al, 2010;Luker et al, 2009). Furthermore, CXCR7-signaling is attenuated or prevented following either cellular arrestin depletion or truncation of the CXCR7 C-terminus (Min et al, 2020;Xu et al, 2019). In addition to the direct activation of signaling proteins / pathways by ACKR3 within the arrestin scaffold, indirect modes of activation seem to exist and involve the Src-kinase-and/or arrestin-dependent transactivation of EGFR (Xu et al, 2019;Salazar et al, 2014;McGinn et al, 2012).…”