Structural basis of CD4 downregulation by HIV-1 Nef

Kwon, Yonghwa; Kaake, Robyn M.; Echeverria, Ignacia; Suarez, Marissa; Shamsabadi, Mohammad Karimian; Stoneham, Charlotte A.; Ramirez, Peter W; Kress, Jacob; Singh, Rajendra; Šali, Andrej; Krogan, Nevan J.; Jia, Xiaofei

doi:10.1038/s41594-020-0463-z

Cited by 47 publications

(77 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“… 39 XL-MS data captured flexible and unresolved components of the Nef-CD4-AP2 crystal structure, and confirmed the observation that Nef serves as a flexible connector between CD4 and clathrin AP2 to promote endocytosis and downregulation of CD4. 39 Finally, XL-MS allows unbiased structure characterization and identification of unknown structural features including additional protein components or post-translational modifications (PTMs). In Yu et al the thiol-cleavable cross-linker 3,3′-dithiobis(sulfo-succinimidylpropionate) (DTSSP) was used to identify vimentin as a transient interactor of the SARS-CoV-1 Spike (S)-ACE2 virus–host protein complex.…”

Section: How Do the Dynamic Structures Of Sars-cov-2 Proteins And Virsupporting

confidence: 64%

Proteomic Approaches to Study SARS-CoV-2 Biology and COVID-19 Pathology

et al. 2021

Self Cite

View full text Add to dashboard Cite

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 , was declared a pandemic infection in March 2020. As of December 2020, two COVID-19 vaccines have been authorized for emergency use by the U.S. Food and Drug Administration, but there are no effective drugs to treat COVID-19, and pandemic mitigation efforts like physical distancing have had acute social and economic consequences. In this perspective, we discuss how the proteomic research community can leverage technologies and expertise to address the pandemic by investigating four key areas of study in SARS-CoV-2 biology. Specifically, we discuss how (1) mass spectrometry-based structural techniques can overcome limitations and complement traditional structural approaches to inform the dynamic structure of SARS-CoV-2 proteins, complexes, and virions; (2) virus−host protein−protein interaction mapping can identify the cellular machinery required for SARS-CoV-2 replication; (3) global protein abundance and post-translational modification profiling can characterize signaling pathways that are rewired during infection; and (4) proteomic technologies can aid in biomarker identification, diagnostics, and drug development in order to monitor COVID-19 pathology and investigate treatment strategies. Systems-level high-throughput capabilities of proteomic technologies can yield important insights into SARS-CoV-2 biology that are urgently needed during the pandemic, and more broadly, can inform coronavirus virology and host biology.

show abstract

Section: How Do the Dynamic Structures Of Sars-cov-2 Proteins And Virsupporting

confidence: 64%

Proteomic Approaches to Study SARS-CoV-2 Biology and COVID-19 Pathology

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, Nef residues 101 to 102 and residue 138 fluctuate less in the SH3 domain complex ( Fig 3F,G) . Hence, the SH3 domain stabilised a large part of the H1 binding site and a region that interacts with CD4 (37) and contributes to Nef:Nef crystal contacts (observed in PDB 1EFN, 1AVV, 1AVZ, 4USW, 3REA, 3D8D), and possibly to dimerisation in vitro (44) ( Fig 3A ). Together these results suggested that SH3 binding selectively decreases the dynamics of Nef regions involved in protein-protein interactions.…”

Section: Resultsmentioning

confidence: 99%

“…A series of structural studies also elucidated how Nef molecules hijack the host cell trafficking machinery by serving as an adaptor between AP1 and MHC-I molecules or between AP2 and CD4 (7,34–37). Akin to its interactions with Src family SH3 domains, Nef uses its core domain in addition to the linear recognition motifs (located on Nef’s flexible regions) to firmly lock onto AP1 or AP2.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, Nef binds to the AP2 α2, β2 and σ2 subunits. Moreover, Nef serves as an adaptor between CD4 and AP2, by using its E 160 xxxLL motif, located in the Nef core domain loop, as mimicry of acidic dileucine motifs of cellular AP2 cargos, while using a core-domain binding pocket to engage part of the CD4 cytoplasmic tail (34,37). However, despite these differences, the binding sites of CD4 and MHC-I on Nef partly overlap (37).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synergy and allostery in ligand binding by HIV-1 Nef

Aldehaiman

Momin

Restouin

et al. 2020

Preprint

View full text Add to dashboard Cite

The Nef protein of human and simian immunodeficiency viruses (HIV and SIV, respectively) boosts viral pathogenicity through its interactions with host cell proteins. Nef has a folded core domain and large flexible regions, each carrying several protein interaction sites. By combining the polyvalency intrinsic to unstructured regions with the binding selectivity and strength of a 3D folded domain, Nef can bind to many different host cell proteins, perturbing their cellular functions. For example, the combination of a linear proline-rich motif and a hydrophobic core domain surface allows Nef to increase affinity and selectivity for particular Src family SH3 domains. Here we investigated whether the interplay between Nef’s flexible regions and its core domain can allosterically influence ligand selection. We found that the flexible regions can bind back to the core domain in different ways, producing distinct conformational states that alter the SH3 domain selectivity and availability of Nef’s functional motifs. The resulting cross-talk might help synergising certain subsets of ligands while excluding others, promoting functionally coherent Nef-bound protein ensembles. Further, we combined proteomic and bioinformatic analyses to identify human proteins that select SH3 domains in the same way as does Nef. We found that only 2–3% of clones from a whole human fetal library displayed a Nef-like SH3 selectivity. However, in most cases this selectivity appears to be achieved by a canonical linear interaction rather than a Nef-like ‘tertiary’ interaction. This analysis suggests that Nef’s SH3 recognition surface has no (or marginally few) cellular counterparts, validating the Nef tertiary binding surface as a promising unique drug target.

show abstract

“…Distinct, non‐overlapping clusters of solutions, as observed in Figure 3a in the XLs_sum parameter (total crosslink score), can indicate insufficient sampling; there are two distinct sets of solutions with different sets of crosslinks satisfied. In comparison, analysis of the more extensive sampling protocol from analysis_extensive (Figure 3b) shows a continuous distribution, indicating a more complete sampling 23,25,26 …”

Section: Integrative Modeling Of the Rna Polymerase II Stalkmentioning

confidence: 98%

Using Integrative Modeling Platform to compute, validate, and archive a model of a protein complex structure

et al. 2020

Self Cite

View full text Add to dashboard Cite

Biology is advanced by producing structural models of biological systems, such as protein complexes. Some systems are recalcitrant to traditional structure determination methods. In such cases, it may still be possible to produce useful models by integrative structure determination that depends on simultaneous use of multiple types of data. An ensemble of models that are sufficiently consistent with the data is produced by a structural sampling method guided by a data-dependent scoring function. The variation in the ensemble of models quantified the uncertainty of the structure, generally resulting from the uncertainty in the input information and actual structural heterogeneity in the samples used to produce the data. Here, we describe how to generate, assess, and interpret ensembles of integrative structural models using our open source Integrative Modeling Platform program (https://integrativemodeling.org).

show abstract

Structural basis of CD4 downregulation by HIV-1 Nef

Cited by 47 publications

References 71 publications

Proteomic Approaches to Study SARS-CoV-2 Biology and COVID-19 Pathology

Proteomic Approaches to Study SARS-CoV-2 Biology and COVID-19 Pathology

Synergy and allostery in ligand binding by HIV-1 Nef

Using Integrative Modeling Platform to compute, validate, and archive a model of a protein complex structure

Contact Info

Product

Resources

About