Molecular recognition in the HIV-1 capsid/cyclophilin A complex.


Abstract

The HIV-1 capsid protein (CA) makes an essential interaction with the human peptidyl prolyl isomerase, cyclophilin A (CypA), that results in packaging of CypA into the virion at a CA to CypA stoichiometry of approximately 10:1. The 231 amino acid residue capsid protein is composed of an amino-terminal CypA binding domain (1 to approximately 151; CA151) and a carboxyl-terminal dimerization domain (approximately 151 to 231). We find that CypA binds dimeric CA and monomeric CA151 with identical intrinsic affinities (K[d] = 16(+/-4) microM). This result demonstrates that capsid dimerization and cyclophilin A binding are not thermodynamically coupled and suggests that the substoichiometric ratio of CypA in the HIV-1 virion results from the intrinsic stability of the CA/CypA complex. In the known co-crystal structure of the CA151/CypA complex, CypA binding is mediated exclusively by an exposed capsid loop that spans residues Pro85 to Pro93. The energetic contributions to CypA binding were quantified for each residue in this loop, and the results demonstrate that the Gly89-Pro90 dipeptide is the primary cyclophilin A recognition motif, with Pro85, Val86, His87, Ala88, and Pro93 also making energetically favorable contacts. These studies reveal that the active site of CypA, which can catalyze the isomerization of proline residues in vitro, also functions as a sequence-specific, protein-binding motif in HIV-1 replication.

Submission Details

ID: AXsUwn94

Submitter: Shu-Ching Ou

Submission Date: Feb. 22, 2019, 12:13 p.m.

Version: 1

Publication Details
Yoo S;Myszka DG;Yeh C;McMurray M;Hill CP;Sundquist WI,J Mol Biol (1997) Molecular recognition in the HIV-1 capsid/cyclophilin A complex. PMID:9223641
Additional Information

Two sets of ΔΔG values are reported. One is from direct calculations using relative Kd, and the other set is reported from the AB-Bind article (DOI: 10.1002/pro.2829)

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1AAF 1992-04-06T00:00:00+0000 0 NUCLEOCAPSID ZINC FINGERS DETECTED IN RETROVIRUSES: EXAFS STUDIES ON INTACT VIRUSES AND THE SOLUTION-STATE STRUCTURE OF THE NUCLEOCAPSID PROTEIN FROM HIV-1
1FGL 1996-11-18T00:00:00+0000 1.8 Cyclophilin A complexed with a fragment of HIV-1 GAG protein
2R05 2007-08-17T00:00:00+0000 2.55 Crystal Structure of ALIX/AIP1 in complex with the HIV-1 YPLASL Late Domain
5HSV 2016-01-26T00:00:00+0000 1.5 X-Ray structure of a CypA-Alisporivir complex at 1.5 angstrom resolution
2FXE 2006-02-05T00:00:00+0000 1.8 X-ray crystal structure of HIV-1 protease CRM mutant complexed with atazanavir (BMS-232632)
1KJ4 2001-12-04T00:00:00+0000 2.9 SUBSTRATE SHAPE DETERMINES SPECIFICITY OF RECOGNITION RECOGNITION FOR HIV-1 PROTEASE: ANALYSIS OF CRYSTAL STRUCTURES OF SIX SUBSTRATE COMPLEXES
6BHR 2017-10-31T00:00:00+0000 2.91 HIV-1 immature CTD-SP1 hexamer in complex with IP6
1SJE 2004-03-03T00:00:00+0000 2.45 HLA-DR1 complexed with a 16 residue HIV capsid peptide bound in a hairpin conformation
1KJF 2001-12-04T00:00:00+0000 2.0 SUBSTRATE SHAPE DETERMINES SPECIFICITY OF RECOGNITION RECOGNITION FOR HIV-1 PROTEASE: ANALYSIS OF CRYSTAL STRUCTURES OF SIX SUBSTRATE COMPLEXES
1SJH 2004-03-03T00:00:00+0000 2.25 HLA-DR1 complexed with a 13 residue HIV capsid peptide

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O12158 POL_HV192
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O12157 GAG_HV192
189.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9Q720 POL_HV1V9
189.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9Q721 GAG_HV1V9
186.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9WC63 POL_HV1S9
186.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9WC62 GAG_HV1S9
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBZ1 POL_HV1M2
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBY3 POL_HV196
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBZ2 GAG_HV1M2
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBY4 GAG_HV196
189.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBZ5 POL_HV1MP
189.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBZ6 GAG_HV1MP
189.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9WC54 POL_HV1S2
189.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9WC53 GAG_HV1S2
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P12498 POL_HV1J3
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P12494 GAG_HV1J3
193.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P18802 POL_HV1ND
193.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P18800 GAG_HV1ND
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04589 POL_HV1EL
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04592 GAG_HV1EL
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q73368 POL_HV1B9
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q73367 GAG_HV1B9
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P12499 POL_HV1Z2
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05961 POL_HV1MN
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05960 POL_HV1C4
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P12495 GAG_HV1Z2
194.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05887 GAG_HV1C4
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P20892 POL_HV1OY
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P20889 GAG_HV1OY
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05888 GAG_HV1MN
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P0C6F2 POL_HV1LW
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04585 POL_HV1H2
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P03367 POL_HV1BR
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04587 POL_HV1B5
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P03366 POL_HV1B1
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q70622 GAG_HV1LW
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04591 GAG_HV1H2
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P03348 GAG_HV1BR
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04593 GAG_HV1B5
195.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P03347 GAG_HV1B1
197.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P03369 POL_HV1A2
197.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P03349 GAG_HV1A2
197.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P20875 POL_HV1JR
197.2 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P20873 GAG_HV1JR
198.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P35963 POL_HV1Y2
198.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05959 POL_HV1RH
198.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P35962 GAG_HV1Y2
198.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05889 GAG_HV1W2
198.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P05890 GAG_HV1RH
200.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P12497 POL_HV1N5
200.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P12493 GAG_HV1N5
192.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P10111 PPIA_RAT
192.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P17742 PPIA_MOUSE
192.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9TTC6 PPIA_RABIT
194.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P14851 PPIA_CRIGR
194.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q8HXS3 PPIA_FELCA
197.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQK3 PPIA_SAGOE
197.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q6DTV9 PPIA_AOTTR
197.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P62936 PPIA_PIG
197.6 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P62935 PPIA_BOVIN
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQK6 PPIA_SYMSY
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q5R8S7 PPIA_PONPY
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P62941 PPIA_PAPAN
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQL1 PPIA_PANTR
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQL2 PPIA_PANPA
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQK7 PPIA_NOMLE
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P62940 PPIA_MACMU
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQK8 PPIA_HYLLA
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P62937 PPIA_HUMAN
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q0ZQL0 PPIA_GORGO
200.0 A,B Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P62938 PPIA_CHLAE
182.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O89940 POL_HV1SE
182.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O41798 POL_HV19N
182.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O89939 GAG_HV1SE
182.0 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P0C1K7 GAG_HV19N
183.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P24740 POL_HV1U4
183.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P24736 GAG_HV1U4
183.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O89290 POL_HV193
183.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O89291 GAG_HV193
183.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q1A267 POL_SIVMB
183.4 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q1A268 GAG_SIVMB
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O93215 POL_HV190
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein O93182 GAG_HV190
184.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QSR3 POL_HV1VI
184.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QSR4 GAG_HV1VI
184.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04588 POL_HV1MA
184.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q75002 POL_HV1ET
184.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein P04594 GAG_HV1MA
184.8 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q75001 GAG_HV1ET
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QBZ9 POL_HV197
187.6 C,D Peptidyl-prolyl cis-trans isomerase A,Gag-Pol polyprotein Q9QC00 GAG_HV197