Interactions between AMOT PPxY motifs and NEDD4L WW domains function in HIV-1 release

Rheinemann, Lara; Thompson, Tuscan; Mercenne, Gaëlle; Paine, Elliott L.; Peterson, Francis C.; Volkman, Brian F.; Alam, Steven L.; Alian, Akram; Sundquist, Wesley I.

doi:10.1016/j.jbc.2021.100975

Cited by 11 publications

(10 citation statements)

References 57 publications

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“…To begin to explore residues in IQGAP1’s WW domain that may directly contact p110α, we used site-directed mutagenesis to examine the role of five individual residues thought to participate in ligand binding in other WW domains [45–49, 53–61]; these residues are represented in ball-and-stick format in Figure 4C. Moving from N-terminal to the C-terminal, the first residue we examined was position 10/Y694.…”

Section: Resultsmentioning

confidence: 99%

“…In many published structures of WW-ligand complexes, the position 10 residue is not observed to make direct contact with the ligand. In both cases where the position 10 residue does contact the ligand, position 10 is an arginine [59, 61]; indeed, the position 10 residue is a basic, positively charged arginine or lysine in most human WW domains. In contrast, position 10 in IQGAP1 is a tyrosine.…”

Section: Discussionmentioning

confidence: 99%

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The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

Bardwell

Paul²,

Yoneda

et al. 2022

Preprint

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IQGAP1 is a multi-domain cancer-associated protein that serves as a scaffold protein for multiple signaling pathways. Numerous binding partners have been found for the calponin homology, IQ and GAP-related domains in IQGAP1. Identification of a binding partner for its WW domain has proven elusive, however, even though a cell-penetrating peptide derived from this domain has marked anti-tumor activity. Here, using in vitro binding assays with human proteins, we show that the WW domain of human IQGAP1 binds directly to the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K). In contrast, the WW domain does not bind to ERK1/2, MEK1/2, or the p85α regulatory subunit of PI3K when p85α is expressed alone. However, the WW domain is able to bind to the p110α/p85α heterodimer when both subunits are co-expressed, as well as to the mutationally activated p110α/p65α heterodimer. We present a model of the structure of the IQGAP1 WW domain, and experimentally identify key residues in the hydrophobic core and beta strands of the WW domain that are required for binding to p110α. These findings contribute to a more precise understanding of IQGAP1-mediated scaffolding, and of how IQGAP1-derived therapeutic peptides might inhibit tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

Bardwell

Paul²,

Yoneda

et al. 2022

Preprint

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“…The P1 site in the AMOTL1 paralog, AMOT, is also indispensable for binding specific WW domain targets 8 and plays a critical role in the function of the protein. 27 Likewise, the P1 site in AMOTL1 may provide some functional advantages to the protein. Fourth, inactivating the P3 site results in a $2-fold binding enhancement which implies that P3 contributes negative entropy to the overall interaction.…”

Section: Discussionmentioning

confidence: 99%

“…More residues are perturbed in the sequence vicinity of the P1 site, a clear indication of more intermolecular interactions at P1 relative to P2 or P3, and evidence that P1 is critical for the assembly of the AMOTL1‐YAP complex. The P1 site in the AMOTL1 paralog, AMOT, is also indispensable for binding specific WW domain targets 8 and plays a critical role in the function of the protein 27 . Likewise, the P1 site in AMOTL1 may provide some functional advantages to the protein.…”

Section: Discussionmentioning

confidence: 99%

Multivalent Angiomotin‐like 1 and Yes‐associated protein form a dynamic complex

2022

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Multivalent complexes formed between the cancer-promoting transcriptional co-activator, Yes-associated protein (YAP), and proteins containing short linear motifs of type PPxY modulate cell proliferation and are attractive therapeutic targets. However, challenges producing PPxY polypeptides containing the full binding domain has limited understanding of the assembly process. Here, we successfully produced a polypeptide containing the complete set of three PPxY binding sites of Angiomotin-like 1 (AMOTL1), a scaffolding protein that regulates the nucleo-cytoplasmic shuttling of YAP via WW-PPxY interactions. Using an array of biophysical techniques including isothermal titration calorimetry, size-exclusion chromatography coupled to multi-angle light scattering, and solution nuclear magnetic resonance spectroscopy, we show that the AMOTL1 polypeptide is partially disordered, and binds the YAP WW domains to form an ensemble of complexes of varying stabilities. The binding process is initiated by the binding of one YAP WW domain to one AMOTL1 PPxY motif and is completed by transient interactions of the second YAP WW domain with a second AMOTL1 PPxY motif to form an equilibrating mixture composed of various species having two YAP sites bound to two conjugate AMOTL1 sites. We rationalize that the transient interactions fine-tune the stability of the complex for rapid assembly and disassembly in response to changes in the local cellular environment.

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“…This suggests that angiomotin serves as a NEDD4L adaptor acting at a stage prior to ESCRT recruitment and function, and further implicates ubiquitylation in the events leading to particle release. The structural basis for interaction of the angiomotin PPXY motifs with NEDD4L WW domains was recently reported [ 174 ].…”

Section: P6: Hiv’s Exit Strategy and Incorporation Of Vprmentioning

confidence: 99%

Advances in HIV-1 Assembly

Lerner

Weaver

Anokhin

et al. 2022

Viruses

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The assembly of HIV-1 particles is a concerted and dynamic process that takes place on the plasma membrane of infected cells. An abundance of recent discoveries has advanced our understanding of the complex sequence of events leading to HIV-1 particle assembly, budding, and release. Structural studies have illuminated key features of assembly and maturation, including the dramatic structural transition that occurs between the immature Gag lattice and the formation of the mature viral capsid core. The critical role of inositol hexakisphosphate (IP6) in the assembly of both the immature and mature Gag lattice has been elucidated. The structural basis for selective packaging of genomic RNA into virions has been revealed. This review will provide an overview of the HIV-1 assembly process, with a focus on recent advances in the field, and will point out areas where questions remain that can benefit from future investigation.

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Interactions between AMOT PPxY motifs and NEDD4L WW domains function in HIV-1 release

Cited by 11 publications

References 57 publications

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

The WW domain of IQGAP1 binds directly to the p110α catalytic subunit of PI 3-kinase

Multivalent Angiomotin‐like 1 and Yes‐associated protein form a dynamic complex

Advances in HIV-1 Assembly

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