Integrative Modeling of a Sin3/HDAC Complex Sub-structure

Banks, Charles A.S.; Zhang, Ying; Miah, Sayem; Hao, Yan; Adams, Mark K.; Wen, Zhihui; Thornton, Janet; Florens, Laurence; Washburn, Michael P.

doi:10.1016/j.celrep.2020.03.080

Cited by 34 publications

(45 citation statements)

References 46 publications

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“…Thus, the additional exon found within SIN3B_1 does not disrupt association between these proteins and the C-terminal half of SIN3B is sufficient for interactions between SIN3B and RBBP4/RBBP7. This is consistent with RBBP4/RBBP7 cross-linking to the SIN3B_2 Sin3a_C domain and is like previous observations indicating that the deletion of the SIN3A HID does not disrupt interactions between SIN3A and RBBP7 (20).…”

Section: Hdac1supporting

confidence: 92%

“…Preparation of Samples for Chemical Cross-linking Mass Spectrometry-For each replicate, 3 confluent 850 cm 2 culture vessels of Flp-In TM -293 cells stably expressing SIN3A-HaloTag or SIN3B_2-Hal-oTag were harvested. Protein was enriched using Magne ® HaloTag ® Beads and cross-linked with disuccinimidyl sulfoxide (DSSO) as previously described (20). Briefly, DSSO (Cayman Chemical Company, Ann Arbor, MI) was added to samples to a final concentration of 5 mM while protein was immobilized on beads.…”

Section: Affinity Purification Of Recombinant Proteins From Flp-in Tmmentioning

confidence: 99%

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Differential Complex Formation via Paralogs in the Human Sin3 Protein Interaction Network

Adams

Banks

Thornton

et al. 2020

Molecular & Cellular Proteomics

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Despite the continued analysis of HDAC inhibitors in clinical trials, the heterogeneous nature of the protein complexes they target limits our understanding of the beneficial and off-target effects associated with their application. Among the many HDAC protein complexes found within the cell, Sin3 complexes are conserved from yeast to humans and likely play important roles as regulators of transcriptional activity. The presence of two Sin3 paralogs in humans, SIN3A and SIN3B, may result in a heterogeneous population of Sin3 complexes and contributes to our poor understanding of the functional attributes of these complexes. Here, we profile the interaction networks of SIN3A and SIN3B to gain insight into complex composition and organization. In accordance with existing data, we show that Sin3 paralog identity influences complex composition. Additionally, chemical crosslinking mass spectrometry identifies domains that mediate interactions between Sin3 proteins and binding partners. The characterization of rare SIN3B proteoforms provides additional evidence for the existence of conserved and divergent elements within human Sin3 proteins. Together, these findings shed light on both the shared and divergent properties of human Sin3 proteins and highlight the heterogeneous nature of the complexes they organize.

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Section: Hdac1supporting

confidence: 92%

Section: Affinity Purification Of Recombinant Proteins From Flp-in Tmmentioning

confidence: 99%

Differential Complex Formation via Paralogs in the Human Sin3 Protein Interaction Network

Adams

Banks

Thornton

et al. 2020

Molecular & Cellular Proteomics

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“…An increasing number of structural methods have come into view, such as cryo-electron microscopy (cryo-EM) and structural MS approaches. For instance, as mentioned above, XL-MS has been used in analyzing Sin3 complex and modeling a structure of this complex at a global level [ 80 ]. In addition, XL-MS [ 158 , 159 ], hydrogen-deuterium exchange MS (HDX-MS) [ 160 , 161 , 162 ], native MS [ 163 , 164 ], native top–down MS [ 165 , 166 ] techniques have been more frequently used for the structural studies of macromolecular protein complexes [ 167 ].…”

Section: Discussionmentioning

confidence: 99%

“…Using an affinity purification mass spectrometry (AP-MS) based approach, Washburn’s group revealed that SUDS3 presents in both Sin3A and Sin3B complexes, while SAP30 is only utilized in the Sin3A complex [ 79 ]. Later, by integrating chemical crosslinking MS (XL-MS) with AP-MS, they modeled the substructure of the Sin3A complex [ 80 ]. Figure 4 B shows that Sin3A protein exists as a backbone so that the other subunits, including HDAC1/2, SAP30 and SUDS3, can assemble.…”

Section: Structures Of Class I Hdacsmentioning

confidence: 99%

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Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

Luo

2020

IJMS

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Class I histone deacetylases (HDACs) are promising targets for epigenetic therapies for a range of diseases such as cancers, inflammations, infections and neurological diseases. Although six HDAC inhibitors are now licensed for clinical treatments, they are all pan-inhibitors with little or no HDAC isoform selectivity, exhibiting undesirable side effects. A major issue with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Except for HDAC8, Class I HDACs (1, 2 and 3) are recruited to large multiprotein complexes to function. Therefore, there are rising needs to develop new, hopefully, therapeutically efficacious HDAC inhibitors with isoform or complex selectivity. Here, upon the introduction of the structures of Class I HDACs and their complexes, we provide an up-to-date overview of the structure-based discovery of Class I HDAC inhibitors, including pan-, isoform-selective and complex-specific inhibitors, aiming to provide an insight into the discovery of additional HDAC inhibitors with greater selectivity, specificity and therapeutic utility.

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SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer

Zhang,

Tang,

Wang

et al. 2024

Advanced Science

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Despite progress significant advances in immunotherapy for some solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive poorly responsive to such interventions, largely due to its highly immunosuppressive tumor microenvironment (TME) with limited CD8+ T cell infiltration. This study explores the role of the epigenetic factor Sin3B in the PDAC TME. Using murine PDAC models, we found that tumor cell‐intrinsic Sin3B loss reshapes the TME, increasing CD8+ T cell infiltration and cytotoxicity, thus impeding tumor progression and enhancing sensitivity to anti‐PD1 treatment. Sin3B‐deficient tumor cells exhibited amplified CXCL9/10 secretion in response to Interferon‐gamma (IFNγ), creating a positive feedback loop via the CXCL9/10‐CXCR3 axis, thereby intensifying the anti‐tumor immune response against PDAC. Mechanistically, extensive epigenetic regulation is uncovered by Sin3B loss, particularly enhanced H3K27Ac distribution on genes related to immune responses in PDAC cells. Consistent with the murine model findings, analysis of human PDAC samples revealed a significant inverse correlation between SIN3B levels and both CD8+ T cell infiltration and CXCL9/10 expression. Notebly, PDAC patients with lower SIN3B expression showed a more favorable response to anti‐PD1 therapy. The findings suggest that targeting SIN3B can enhance cytotoxic T cell infiltration into the tumor site and improve immunotherapy efficacy in PDAC, offering potential avenues for therapeutic biomarker or target in this challenging disease.

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Integrative Modeling of a Sin3/HDAC Complex Sub-structure

Cited by 34 publications

References 46 publications

Differential Complex Formation via Paralogs in the Human Sin3 Protein Interaction Network

Differential Complex Formation via Paralogs in the Human Sin3 Protein Interaction Network

Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)

SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer

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