Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization

Joshua Holcomb; Yuanyuan Jiang; Xiaoqing Guan; Laura Trescott; Guorong Lu; Yuning Hou; Shuo Wang; Joseph Brunzelle; Nualpun Sirinupong; Chunying Li; Zhe Yang

doi:10.1016/j.bbrc.2014.04.085

Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization

Joshua Holcomb, Yuanyuan Jiang, Xiaoqing Guan, Laura Trescott, Guorong Lu, Yuning Hou, Shuo Wang, Joseph Brunzelle, Nualpun Sirinupong, Chunying Li^*, Zhe Yang

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

The formation of CXCR2-NHERF1-PLCβ2 macromolecular complex in neutrophils regulates CXCR2 signaling and plays a key role in neutrophil chemotaxis and transepithelial neutrophilic migration. However, NHERF1 by itself, with only two PDZ domains, has a limited capacity in scaffolding the multiprotein-complex formation. Here we report the crystal structure of the NHERF1 PDZ2 domain in complex with the C-terminal CXCR2 sequence. The structure reveals that the PDZ2-CXCR2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four CXCR2 residues contributing to specific interactions. The structure also reveals two probable modes of PDZ2 dimerization where the two canonical ligand-binding pockets are well separated and orientated in a unique parallel fashion. This study provides not only the structural basis for the PDZ-mediated NHERF1-CXCR2 interaction, but also an additional example of how PDZ domains may dimerize, which both could prove valuable in understanding NHERF1 complex-scaffolding function in neutrophils.

Original language	English (US)
Pages (from-to)	169-174
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	448
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2014.04.085
State	Published - May 30 2014

Funding

This study was supported by the Leukemia Research Foundation , Aplastic Anemia & MDS International Foundation , and American Heart Association Grant number 0835085N (to Z.Y.) and from the Elsa U. Pardee Foundation , American Heart Association , and American Cancer Society Institutional Research Grant #11-053-01-IRG (to C.L.).

Keywords

CXCR2
Dimerization
NHERF1
Neutrophil
Scaffold protein
X-ray crystallography

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

Access to Document

10.1016/j.bbrc.2014.04.085

Cite this

Holcomb, J., Jiang, Y., Guan, X., Trescott, L., Lu, G., Hou, Y., Wang, S., Brunzelle, J., Sirinupong, N., Li, C., & Yang, Z. (2014). Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization. Biochemical and Biophysical Research Communications, 448(2), 169-174. https://doi.org/10.1016/j.bbrc.2014.04.085

@article{de0d898513bd4016bd9ad1c0195dd123,

title = "Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization",

abstract = "The formation of CXCR2-NHERF1-PLCβ2 macromolecular complex in neutrophils regulates CXCR2 signaling and plays a key role in neutrophil chemotaxis and transepithelial neutrophilic migration. However, NHERF1 by itself, with only two PDZ domains, has a limited capacity in scaffolding the multiprotein-complex formation. Here we report the crystal structure of the NHERF1 PDZ2 domain in complex with the C-terminal CXCR2 sequence. The structure reveals that the PDZ2-CXCR2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four CXCR2 residues contributing to specific interactions. The structure also reveals two probable modes of PDZ2 dimerization where the two canonical ligand-binding pockets are well separated and orientated in a unique parallel fashion. This study provides not only the structural basis for the PDZ-mediated NHERF1-CXCR2 interaction, but also an additional example of how PDZ domains may dimerize, which both could prove valuable in understanding NHERF1 complex-scaffolding function in neutrophils.",

keywords = "CXCR2, Dimerization, NHERF1, Neutrophil, Scaffold protein, X-ray crystallography",

author = "Joshua Holcomb and Yuanyuan Jiang and Xiaoqing Guan and Laura Trescott and Guorong Lu and Yuning Hou and Shuo Wang and Joseph Brunzelle and Nualpun Sirinupong and Chunying Li and Zhe Yang",

note = "Funding Information: This study was supported by the Leukemia Research Foundation , Aplastic Anemia & MDS International Foundation , and American Heart Association Grant number 0835085N (to Z.Y.) and from the Elsa U. Pardee Foundation , American Heart Association , and American Cancer Society Institutional Research Grant #11-053-01-IRG (to C.L.).",

year = "2014",

month = may,

day = "30",

doi = "10.1016/j.bbrc.2014.04.085",

language = "English (US)",

volume = "448",

pages = "169--174",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Elsevier B.V.",

number = "2",

}

Holcomb, J, Jiang, Y, Guan, X, Trescott, L, Lu, G, Hou, Y, Wang, S, Brunzelle, J, Sirinupong, N, Li, C & Yang, Z 2014, 'Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization', Biochemical and Biophysical Research Communications, vol. 448, no. 2, pp. 169-174. https://doi.org/10.1016/j.bbrc.2014.04.085

TY - JOUR

T1 - Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization

AU - Holcomb, Joshua

AU - Jiang, Yuanyuan

AU - Guan, Xiaoqing

AU - Trescott, Laura

AU - Lu, Guorong

AU - Hou, Yuning

AU - Wang, Shuo

AU - Brunzelle, Joseph

AU - Sirinupong, Nualpun

AU - Li, Chunying

AU - Yang, Zhe

N1 - Funding Information: This study was supported by the Leukemia Research Foundation , Aplastic Anemia & MDS International Foundation , and American Heart Association Grant number 0835085N (to Z.Y.) and from the Elsa U. Pardee Foundation , American Heart Association , and American Cancer Society Institutional Research Grant #11-053-01-IRG (to C.L.).

PY - 2014/5/30

Y1 - 2014/5/30

N2 - The formation of CXCR2-NHERF1-PLCβ2 macromolecular complex in neutrophils regulates CXCR2 signaling and plays a key role in neutrophil chemotaxis and transepithelial neutrophilic migration. However, NHERF1 by itself, with only two PDZ domains, has a limited capacity in scaffolding the multiprotein-complex formation. Here we report the crystal structure of the NHERF1 PDZ2 domain in complex with the C-terminal CXCR2 sequence. The structure reveals that the PDZ2-CXCR2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four CXCR2 residues contributing to specific interactions. The structure also reveals two probable modes of PDZ2 dimerization where the two canonical ligand-binding pockets are well separated and orientated in a unique parallel fashion. This study provides not only the structural basis for the PDZ-mediated NHERF1-CXCR2 interaction, but also an additional example of how PDZ domains may dimerize, which both could prove valuable in understanding NHERF1 complex-scaffolding function in neutrophils.

AB - The formation of CXCR2-NHERF1-PLCβ2 macromolecular complex in neutrophils regulates CXCR2 signaling and plays a key role in neutrophil chemotaxis and transepithelial neutrophilic migration. However, NHERF1 by itself, with only two PDZ domains, has a limited capacity in scaffolding the multiprotein-complex formation. Here we report the crystal structure of the NHERF1 PDZ2 domain in complex with the C-terminal CXCR2 sequence. The structure reveals that the PDZ2-CXCR2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four CXCR2 residues contributing to specific interactions. The structure also reveals two probable modes of PDZ2 dimerization where the two canonical ligand-binding pockets are well separated and orientated in a unique parallel fashion. This study provides not only the structural basis for the PDZ-mediated NHERF1-CXCR2 interaction, but also an additional example of how PDZ domains may dimerize, which both could prove valuable in understanding NHERF1 complex-scaffolding function in neutrophils.

KW - CXCR2

KW - Dimerization

KW - NHERF1

KW - Neutrophil

KW - Scaffold protein

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=84901611873&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901611873&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2014.04.085

DO - 10.1016/j.bbrc.2014.04.085

M3 - Article

C2 - 24768637

AN - SCOPUS:84901611873

SN - 0006-291X

VL - 448

SP - 169

EP - 174

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 2

ER -

Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this