CoChat
Sign Up
Cited by 95HIV Research and TreatmentLipid Membrane Structure and BehaviorCellular transport and secretion

Structure of the myristylated human immunodeficiency virus type 2 matrix protein and the role of phosphatidylinositol-(4,5)-bisphosphate in membrane targeting

Open access
Saad, Jamil S., Ablan, Sherimay D., Ghanam, Ruba H., Kim, Andrew, Andrews, Kalola, Nagashima, Kunio, Soheilian, Ferri, Freed, Eric O. +1 more·2008·Journal of Molecular Biology
DOI 10.1016/j.jmb.2008.07.027PMC PMC2581411
Open this paper in CoChat — free account

Abstract

During the late phase of retroviral replication, newly synthesized Gag proteins are targeted to the plasma membrane (PM), where they assemble and bud to form immature virus particles. Membrane targeting by human immunodeficiency virus type 1 (HIV-1) Gag is mediated by the PM marker molecule phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)], which is capable of binding to the matrix (MA) domain of Gag in an extended lipid conformation and of triggering myristate exposure. Here, we show that, as observed previously for HIV-1 MA, the myristyl group of HIV-2 MA is partially sequestered within a narrow hydrophobic tunnel formed by side chains of helices 1, 2, 3, and 5. However, the myristate of HIV-2 MA is more tightly sequestered than that of the HIV-1 protein and does not exhibit concentration-dependent exposure. Soluble PI(4,5)P(2) analogs containing truncated acyl chains bind HIV-2 MA and induce minor long-range structural changes but do not trigger myristate exposure. Despite these differences, the site of HIV-2 assembly in vivo can be manipulated by enzymes that regulate PI(4,5)P(2) localization. Our findings indicate that HIV-1 and HIV-2 are both targeted to the PM for assembly via a PI(4,5)P(2)-dependent mechanism, despite differences in the sensitivity of the MA myristyl switch, and suggest a potential mechanism that may contribute to the poor replication kinetics of HIV-2.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.jmb.2008.07.027

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gag assembly depends on PIP2 in several retroviruses including MPMV, MLV, ASV, FIV, and HIV-2.

    “Besides HIV-1, the dependence of Gag assembly on PIP2 has also been observed in several other retroviruses, including MPMV; MLV, ASV, FIV, and HIV-2”

    From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Saad et al. 2008

    The Results section (‘The subcellular site of HIV-2 Gag assembly is regulated by PI(4,5)P2’; page unavailable) reports that perturbing PI(4,5)P2 reduced HIV-2 particle production and altered where HIV-2 assembled. Our copy does not establish PI(4,5)P2-dependent assembly for the other listed retroviruses—MPMV, MLV, ASV, or FIV. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 65

  1. [1]Lemey P Pybus OG Wang B Saksena NK Salemi M Vandamme A-M Tracing the origin and history of the HIV-2 epidemic. Proc. Natl Acad. Sci. USA 2003 100 6588 6592 12743376 PMC164491
  2. [2]Poulsen AG Aaby P Larsen O Jensen H Naucler A Lisse IM 9-year HIV-2-associated mortality in an urban community in Bissau, West Africa. Lancet 1997 349 911 914 9093252
  3. [3]Schim van der Loeff MF Jaffar S Aveika AA Sabally S Corrah T Harding E Mortality of HIV-1, HIV-2 and HIV-1/HIV-2 dually infected patients in a clinic-based cohort in The Gambia. AIDS 2002 16 1775 1783 12218389
  4. [4]Ariyoshi K Jaffar S Alabi AS Berry N Schim van der Loeff MF Sabally S Plasma RNA viral load predicts the rate of CD4 T cell decline and death in HIV-2-infected patients in West Africa. AIDS 2000 14 339 344 10770535
  5. [5]Mellors JW Rinaldo CR Gupta P Jr White RM Todd JA Kingsley LA Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996 272 1167 1170 8638160
  6. [6]Popper SJ Sarr AD Travers KU Gueye-Ndiaye A Mboup S Essex ME Kanki PJ Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2. J. Infect. Dis 1999 180 1116 1121 10479138
  7. [7]Vesanen M Stevens CE Taylor PE Rubinstein P Saksela K Stability in controlling viral replication identifies long-term nonprogressors as a distinct subgroup among human immunodeficiency virus type 1-infected persons. J. Virol 1996 70 9035 9040 8971039 PMC191007
  8. [8]Duvall MG Precopio ML Ambrozak DA Jaye A McMichael AJ Whittle HC Polyfunctional T cell responses are a hallmark of HIV-2 infection. Eur. J. Immunol 2008 38 350 363 18200635 PMC2362391
  9. [9]Blaak H van der Ende ME Boers PHM Schuitemaker H Osterhaus ADME In vitro replication capacity of HIV-2 variants from long-term aviremic individuals. Virology 2006 353 144 154 16814357
  10. [10]Blaak H Boers PHM van der Ende ME Schuitemaker H Osterhaus ADME CCR5-restricted HIV type 2 variants from long-term aviremic individuals are less sensitive to inhibition by β-chemokines than low pathogenic HIV type 1 variants. AIDS Res. Human Retroviruses 2008 24 473 484 18327978
  11. [11]Morikawa Y Goto T Yasuoka D Momose F Matano T Defect of human immunodeficiency virus type 2 Gag assembly in Saccharomyces cerevisiae. J. Virol 2007 81 9911 9921 17609278 PMC2045428
  12. [12]Gheysen D Jacobs E de Foresta F Thiriart C Francotte M Thines D De Wilde M Assembly and release of HIV-1 precursor Pr55gag virus-like particles from recombinant baculovirus-infected insect cells. Cell 1989 59 103 112 2676191
  13. [13]Ganser-Pomillos BK Yeager M Sundquist WI The structural biology of HIV assembly. Curr. Opin. Struct. Biol 2008 18 203 217 18406133 PMC2819415
  14. [14]Dong X Li H Derdowski A Ding L Burnett A Chen X AP-3 directs the intracellular trafficking of HIV-1 Gag and plays a key role in particle assembly. Cell 2005 120 663 674 15766529
  15. [15]Hermida-Matsumoto L Resh MD Localization of human immunodeficiency virus type 1 Gag and Env at the plasma membrane by confocal imagine. J. Virol 2000 74 8670 8679 10954568 PMC116378
  16. [16]Kiernan RE Ono A Englund G Freed EO Role of matrix in an early postentry step in the human immunodeficiency virus type 1 life cycle. J. Virol 1998 72 4116 4126 9557701 PMC109641
  17. [17]Kiernan RE Ono A Freed EO Reversion of a human immunodeficiency virus type 1 matrix mutation affecting Gag membrane binding, endogenous reverse transcriptase activity, and virus infectivity. J. Virol 1999 73 4728 4737 10233933 PMC112515
  18. [18]Ono A Orenstein JM Freed EO Role of the Gag matrix domain in targeting human immuno-deficiency virus type 1 assembly. J. Virol 2000 74 2855 2866 10684302 PMC111776
  19. [19]Scarlata S Cater C Role of HIV-1 Gag domains in viral assembly. Biochim. Biophys. Acta 2003 1614 62 72 12873766
  20. [20]Ehrlich LS Fong S Scarlata S Zybarth G Carter C Partitioning of HIV-1 Gag and Gag-related proteins to membranes. Biochemistry 1996 35 3933 3943 8672424
  21. [21]Ono A Freed EO Plasma membrane rafts play a critical role in HIV-1 assembly and release. Proc. Natl. Acad. Sci. USA 2001 98 13925 13930 11717449 PMC61143
  22. [22]Spearman P Horton R Ratner L Kuli-Zade I Membrane binding of human immunodeficiency virus type 1 matrix protein in vivo supports a conformational myristyl switch mechanism. J. Virol 1997 71 6582 6592 9261380 PMC191936
  23. [23]Zhou W Parent LJ Wills JW Resh MD Identification of a membrane-binding domain within the amino-terminal region of human immuno-deficiency virus type 1 Gag protein which interacts with acidic phospholipids. J. Virol 1994 68 2556 2569 8139035 PMC236733
  24. [24]Bouamr F Scarlata S Carter CA Role of myristylation in HIV-1 Gag assembly. Biochemistry 2003 42 6408 6417 12767222
  25. [25]Ono A Ablan SD Lockett SJ Nagashima K Freed EO Phosphatidylinositol (4,5) bisphosphate regulates HIV-1 Gag targeting to the plasma membrane. Proc. Natl Acad. Sci. USA 2004 101 14889 14894 15465916 PMC522033
  26. [26]Jouvenet N Neil SJD Bess C Johnson MC Virgen CA Simon SM Bieniasz PD Plasma membrane is the site of productive HIV-1 particle assembly. PLoS Biol 2006 4 e435 17147474 PMC1750931
  27. [27]Demirov D Freed EO Retrovirus budding. Virus Res 2004 106 87 102 15567490
  28. [28]Freed EO HIV-1 Gag proteins: diverse functions in the virus life cycle. Virology 1998 251 1 15 9813197
  29. [29]Saad JS Miller J Tai J Kim A Ghanam RH Summers MF Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc. Natl Acad. Sci. USA 2006 103 11364 11369 16840558 PMC1544092
  30. [30]Saad JS Loeliger E Luncsford P Liriano M Tai J Kim A Point mutations in the HIV-1 matrix protein turn off the myristyl switch. J. Mol. Biol 2007 366 574 585 17188710 PMC1853300
  31. [31]Adamson CS Freed EO Human immunodeficiency virus type 1 assembly, release and maturation. Adv. Pharmacol 2007 55 347 387 17586320
  32. [32]Tang C Loeliger E Luncsford P Kinde I Beckett D Summers MF Entropic switch regulates myristate exposure in the HIV-1 matrix protein. Proc. Natl Acad. Sci. USA 2004 101 517 522 14699046 PMC327179
  33. [34]Hermida-Matsumoto L Resh MD Human immunodeficiency virus type 1 protease triggers a myristoyl switch that modulates membrane binding fo Pr55gag and p17MA. J. Virol 1999 73 1902 1908 9971769 PMC104431
  34. [35]Paillart J-C Gottlinger HG Opposing effects of human immunodeficiency virus type 1 matrix mutations support a myristyl switch model of Gag membrane targeting. J. Virol 1999 73 2604 2612 10074105 PMC104015
  35. [36]Resh MD A myristoyl switch regulates membrane binding of HIV-1 Gag. Proc. Natl Acad. Sci. USA 2004 101 417 418 14707265 PMC327161
  36. [37]Ebbets-Reed D Scarlata S Carter CA The major homology region of the HIV-1 Gag precursor influences membrane affinity. Biochemistry 1996 35 14268 14275 8916912
  37. [38]Liang C Hu J Russell RS Roldan A Kleiman L Wainberg MA Characterization of a putative α-helix across the capsid-SP1 boundary that is critical for the multimerization of human immunodeficiency virus type 1 Gag. J. Virol 2002 76 11729 11737 12388733 PMC136778
  38. [40]Ono A Demirov D Freed EO Relationship between human immunodeficiency virus type-1 Gag multimerization and membrane binding. J. Virol 2000 74 5142 5150 10799589 PMC110867
  39. [41]Martin TFJ PI(4,5)P2 regulation of surface membrane traffic. Curr. Opin. Cell Biol 2001 13 493 499 11454457
  40. [42]Behnia R Munro S Organelle identity and the signposts for membrane traffic. Nature 2005 438 597 604 16319879
  41. [43]McLaughlin S Murray D Plasma membrane phosphoinositide organization by protein electrostatics. Nature 2005 438 605 611 16319880
  42. [45]Janmey PA IIda K Yin HL Stossel TP Phosphoinositide micelles and polyphosphoinositide-containing vesicles dissociate endogenous gelsolin–actin complexes and promote actin assembly from the fast-growing end of actin filaments blocked by gelsolin. J. Biol. Chem 1987 262 12228 12236 3040735
  43. [46]Kutateladze T Overduin M Structural mechanism of endosome docking by the FYVE domain. Science 2001 291 1793 1796 11230696
  44. [47]Kutateladze T Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain. Biochim. Biophys. Acta 2006 1761 868 877 16644267 PMC2740714
  45. [48]Lee SA Kovacs J Stahelin RV Cheever ML Overduin M Setty TG Molecular mechanism of membrane docking by the Vam7p PX domain. J. Biol. Chem 2006 281 37091 37101 16984909 PMC1838524
  46. [49]Wüthrich K NMR of Proteins and Nucleic Acids 1986 John Wiley & Sons New York, NY
  47. [50]Kay LE Clore GM Bax A Gronenborn AM Four-dimensional heteronuclear triple-resonance NMR spectroscopy of interleukin-1β in solution. Science 1990 249 411 414 2377896
  48. [51]Hill CP Worthylake D Bancroft DP Christensen AM Sundquist WI Crystal structures of the trimeric HIV-1 matrix protein: implications for membrane association. Proc. Natl Acad. Sci. USA 1996 93 3099 3104 8610175 PMC39768
  49. [53]Kinnunen PKJ Koiv A Lehtonen JYA Rytomaa M Mustonen P Lipid dynamics and peripheral interactions of proteins with membrane surfaces. Chem. Phys. Lipids 1994 73 181 207 8001181
  50. [54]Rytomaa M Kinnunen PKJ Reversibility of the binding of cytochrome c to liposomes. J. Biol. Chem 1995 270 3197 3202 7852404
  51. [56]Freed EO Orenstein JM Buckler-White AJ Martin MA Single amino acid changes in the human immunodeficiency virus type 1 matrix protein block virus particle production. J. Virol 1994 68 5311 5320 8035531 PMC236481
  52. [57]Ono A Freed EO Binding of human immunodeficiency virus type 1 Gag to membrane: role of the matrix amino terminus. J. Virol 1999 73 4136 4144 10196310 PMC104193
  53. [58]Ono A Huang M Freed EO Characterization of human immunodeficiency virus type 1 matrix revertants: effects on virus assembly, Gag processing, and Env incorporation into virions. J. Virol 1997 71 4409 4418 9151831 PMC191659
  54. [59]Delaglio F Grzesiek S Vuister GW Zhu G Pfeifer J Bax A NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR 1995 6 277 293 8520220
  55. [60]Johnson BA Blevins RA NMRView: a computer program for the visualization and analysis of NMR data. J. Biomol. NMR 1994 4 603 614 22911360
  56. [62]Ishii Y Markus MA Tycko R Controlling residual dipolar couplings in high-resolution NMR of proteins by strain induced alignment in a gel. J. Biomol. NMR 2001 21 141 151 11727977
  57. [63]Chou JJ Gaemers S Howder B Louis JM Bax A A simple apparatus for generating stretched polyacrylamide gels, yielding uniform alignment of proteins and detergent micelles. J. Biomol. NMR 2001 21 377 382 11824758
  58. [64]Johnson ML Faunt LM Parameter estimation by least-squares methods. Methods Enzymol 1992 210 1 37 1584035
  59. [65]Adachi A Gendelman HE Koenig S Folks T Willey R Rabson A Martin MA Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol 1986 59 284 291 3016298 PMC253077
  60. [66]Clavel F Guyader M Guetard D Salle M Montagnier L Alizon M Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature 1986 324 691 695 3025743
  61. [67]Kisseleva MV Cao L Majerus PW Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits Akt/protein kinase B phosphorylation and leads to apoptotic cell death. J. Biol. Chem 2002 277 6266 6272 11706019
  62. [68]Brown FD Rozelle AL Yin HL Balla T Donaldson JG Phosphatidylinositol 4,5-bisphosphate and Arf6-regulated membrane traffic. J. Cell Biol 2001 154 1007 1017 11535619 PMC2196179
  63. [69]Freed EO Martin MA Evidence for a functional interaction between the V1/V2 and C4 domains of human immunodeficiency virus type 1 envelope glycoprotein gp120. J. Virol 1994 68 2503 2512 8139032 PMC236728
  64. [70]Minassian AA Kalyanaraman VS Gallo RC Popovic M Monoclonal antibodies against human immunodeficiency virus (HIV) type 2 core proteins: cross-reactivity with HIV type 1 and simian immunodeficiency virus. Proc. Natl Acad. Sci. USA 1988 85 6939 6943 2457921 PMC282094
  65. [71]Gonda MA Aaronson SA Ellmore N Zeve VH Nagashima K Ultrastructural studies of surface features of human normal and tumor cells in tissue culture by scanning transmission electron microscopy. J. Natl Cancer Inst 1976 56 245 263 1255758

Cited by

Sorted by citations

Authors
Saad, J. S., Ablan, S. D., Ghanam, R. H., Kim, A., Andrews, K., Nagashima, K., Soheilian, F., Freed, E. O., & Summers, M. F.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Frederick National Laboratory for Cancer Research (US)
  • National Cancer Institute (US)
Corresponding author
  • Freed, Eric O.
  • Summers, Michael F.
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2008-10
Volume
382
Issue
2
Pages
434-447
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2008.07.027
PMC
PMC2581411
OpenAlex
W2154140185
Cited by
95
References
6
Citations by year
2025: 2 · 2024: 5 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 5 · 2016: 11 · 2015: 5 · 2014: 8 · 2013: 7 · 2012: 7
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (AI30917)
  • National Cancer Institute (N01-CO-12400)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
HIV-2, HIV-1, matrix protein, phosphatidylinositol 4,5-bisphosphate, membrane targeting, Gag protein, protein-lipid interactions, hydrophobic tunnel, viral assembly, plasma membrane, retroviral replication
MeSH terms
Animals, Cell Membrane, Humans, Models, Molecular, Myristates, Protein Conformation, Viral Proteins, Virus Replication, HIV-2, Phosphatidylinositol 4,5-Diphosphate, Nuclear Magnetic Resonance, Biomolecular

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review