Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

Filippakopoulos, P.; Low, Andrew; Sharpe, Timothy D.; Uppenberg, J.; Yao, Shenggen; Kuang, Zhihe; Savitsky, P.; Lewis, Rowena S.; Nicholson, Sandra E.; Norton, Raymond S.; Bullock, Alex N.

doi:10.1016/j.jmb.2010.06.017

Cited by 63 publications

(90 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). This structurally divergent protein face forms the binding interface in TRIM21,Gustavus, and SPSB1-4 proteins, the interactions of which with their binding partners have been structurally characterized (24,26,27). In primate TRIM5α, the residues that display strong positive selection in recent evolution as well as sequence insertion sites map to the same protein surface (10,11,13), offering strong evidence that the TRIM5α PRYSPRY uses the same interface for binding to the retroviral capsids (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Biris¹,

Yang

Taylor³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tripartite motif protein TRIM5α blocks retroviral replication after cell entry, and species-specific differences in its activity are determined by sequence variations within the C-terminal B30.2/ PRYSPRY domain. Here we report a high-resolution structure of a TRIM5α PRYSPRY domain, the PRYSPRY of the rhesus monkey TRI-M5α that potently restricts HIV infection, and identify features involved in its interaction with the HIV capsid. The extensive capsidbinding interface maps on the structurally divergent face of the protein formed by hypervariable loop segments, confirming that TRIM5α evolution is largely determined by its binding specificity. Interactions with the capsid are mediated by flexible variable loops via a mechanism that parallels antigen recognition by IgM antibodies, a similarity that may help explain some of the unusual functional properties of TRIM5α. Distinctive features of this pathogenrecognition interface, such as structural plasticity conferred by the mobile v1 segment and interaction with multiple epitopes, may allow restriction of divergent retroviruses and increase resistance to capsid mutations.

show abstract

Section: Resultsmentioning

confidence: 99%

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Biris¹,

Yang

Taylor³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…U87MG (H) cells were transfected with 20 nM control or SPSB1 siRNA and pCAGA 12 -luc for 24 h and subsequently infected with adenovirus carrying TGF-␤-driven tdTomato expression (pAd-CAGA-tdTomato) for another 24 h. Cells were then treated with or without TGF-␤ (2 ng/ml) for a further 24 h. Live cell images were taken using a fluorescent microscope (magnification, ϫ20). ent in multiple target proteins (37,57,58), it is possible that this represents a direct interaction between SPSB1 and T␤RII. Alternatively, another (as yet unknown) protein may act as an adaptor to bring SPSB1 to the T␤RII complex.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that SPSB1 and -2 recognize a similar sequence motif in Par4 and iNos: Glu/Asp-Leu/Ile-AsnAsn-Asn-Leu ((E/D)(L/I)NNN)). In particular, the Asn-AsnAsn sequence was crucial for their interaction (37,57,58). Our sequence alignment shows that T␤RII shares no overall sequence similarity with Par4 but contains a stretch of Asn 234 -Ile-Asn-His-Asn-Thr 239 (NINHNT) at the N terminus of the intracellular domain of the receptor.…”

Section: Tgf-␤ Induces Spsb1 Transcription Which Acts In a Feedback mentioning

confidence: 99%

SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

Liu

Nheu

Luwor

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: TGF-␤ signaling is tightly controlled by different regulators along its signaling cascade. Results: SPSB1 interacts and reduces the protein levels of T␤RII, which results in decreasing TGF-␤ signaling. Conclusion: SPSB1 acts as a new regulatory component of the TGF-␤ signaling pathway that targets T␤RII for degradation and provides fine control of its signaling. Significance: This is the first specific T␤RII negative regulator reported.

show abstract

“…and Asn27) [2]. Further binding studies by surface plasmon resonance (SPR) experiments revealed the linear DINNN peptide bound to SPSB2 with a K D of 318 nM [3], suggesting that the flanking residues of the DINNN sequence in the N-terminal region of iNOS contributed to its low nanomolar binding affinity to SPSB2.…”

mentioning

confidence: 99%

Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction

et al. 2016

Self Cite

View full text Add to dashboard Cite

Edited by Barry HalliwellSPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and 19 F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.Keywords: anti-infective; cyclic peptide; inducible nitric oxide synthase; redox-stable; SPRY domain of the SOCS-box protein 2 SPSB2 protein plays a key role in modulating the lifetime of iNOS in macrophages during infection [1]. It acts as a negative regulator that recruits an E3 ubiquitin ligase complex that polyubiquitinates iNOS and thereby mediates its proteasomal degradation [1]. SPSB2-deficient macrophages exhibit prolonged iNOS expression, NO production and ultimately enhanced killing of persistent pathogens such as Leishmania major parasites and Mycobacterium tuberculosis, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as a new class of anti-infectives [1].Kuang et al. [1] showed that a linear peptide from the disordered N-terminal region of iNOS, KEEK-DINNNVKKT, bound to SPSB2 with a K D of 13 nM, and that the most important residues mediating this interaction were DINNN, in particular the first, third and fifth residues of this sequence motif. In addition, structural studies by X-ray crystallography revealed that the SPRY domain of SPSB2 binds to Asp184, Asn186 and Asn188 of the DINNN sequence of the VASA peptide, the same motif as in the N-terminal region of iNOS (where the corresponding residues are Asp23, Asn25Abbreviations SPSB2, SPRY domain of the SOCS-box protein 2; iNOS, inducible nitric oxide synthase; SPR, surface plasmon

show abstract

Structural Basis for Par-4 Recognition by the SPRY Domain- and SOCS Box-Containing Proteins SPSB1, SPSB2, and SPSB4

Cited by 63 publications

References 34 publications

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction

Contact Info

Product

Resources

About