Calvin Yip
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- Characterizing protein complexes involved in chromatin modification and epigenetic regulation
- Dissecting the regulatory mechanisms of autophagy degradation
- Investigating the molecular bases of rare diseases
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
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Conserved from yeast to humans and composed of six subunits (Elp1 – Elp6), Elongator catalyzes the modification of the anticodon loop of transfer RNAs (tRNAs) and in turn regulates messenger RNA (mRNA) decoding efficiency. By examining human Elongator and its subunits by single-particle electron microscopy (EM), co-purification and pulldown assays, and substrate binding assays, we found that the complex shares similar overall morphologies as the yeast counterpart, and the accessory proteins serve to stabilize ELP3 and improve the binding of substrate tRNAs. Collectively, our work generated insights into the assembly process of this complex and established a platform for characterizing human Elongator and its variants.The heterotrimeric TINTIN complex is an important regulator of transcriptional elongation. Composed of the Eaf3, Eaf5, and Eaf7 proteins, TINTIN exists as both as a module within the NuA4 histone acetyltransferase complex as well as independently. TINTIN is targeted to chromatin through Eaf3, a chromodomain-containing protein that is shared with the Rpd3S histone deacetylase complex. A combination of co-immunoprecipitation and hydrogen deuterium exchange mass spectrometry (HDX-MS) revealed that upon binding Eaf5 and Eaf7, Eaf3 undergoes conformational changes which improves its affinity towards nucleosomes trimethylated at Lys 36 of histone H3 (H3K36me3). Negative stain EM analysis of TINTIN in complex with nucleosomes revealed that TINTIN binds to the disc edge of nucleosomes with increased specificity in the presence of H3K36me3. Together, this work provides molecular insights into the dynamics of TINTIN and the mechanism by which its interactions with chromatin are regulated.The class IB phosphoinositide 3-kinase (PI3K), PI3Kγ, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kγ function is the association of the p110γ catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein–coupled receptors. The cryo–electron microscopy structure of p110γ-p101 reveals the novel architecture of the p101 regulatory subunit and demonstrates a unique assembly that is distinct from other class I PI3K complexes.
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Macroautophagy, often referred to as autophagy, is a non-selective degradation mechanism used by eukaryotic cells to recycle cytoplasmic material and maintain homeostasis. Upregulated under starvation to generate molecular building blocks for ongoing cellular processes, this pathway requires the coordinated action of six multi-protein complexes, the Atg1/ULK1 complex being the first. Although, the Atg1 complex has been extensively studied in Saccharomyces cerevisiae, far less is known about the biochemical and structural properties of its mammalian counterpart, the ULK1 complex. Unlike the S. cerevisiae Atg1 complex which contains five subunits (Atg1, Atg13, Atg17, Atg29, and Atg31), the ULK1 complex consists of four proteins (ULK1, FIP200/RB1CC1, ATG13, and ATG101) that are technically more challenging to study. In this thesis, I characterized the Atg1 complex from fission yeast, Schizosaccharomyces pombe, as the composition of proteins resembles the mammalian ULK1 complex but is more amenable to biochemical analyses. The Atg1 complex in S. pombe is composed of Atg1 (ULK1 counterpart), Atg13, Atg17 (FIP200 counterpart) and Atg101. We found that the interactions between Atg1, Atg17, and Atg13 are conserved while Atg101 does not replace Atg29 and Atg31. Instead, Atg101 binds to Atg1 and the HORMA domain of Atg13. Furthermore, Atg101 was previously shown to contain a conserved loop, termed the WF finger, postulated to bind and recruit downstream autophagy-related proteins and effectors. Using affinity purification mass spectrometry, we further investigated the potential interacting partners of S. pombe Atg101 under autophagy-inducing and non-inducing conditions. We obtained 625 proteins that co-purified with Atg101-GFP from cells grown in defined media. We used in vitro pairwise studies to confirm the interaction between Atg101 and prey proteins. 9 of the 16 proteins tested were confirmed including Fkh1, an FKBP-type peptidyl-prolyl cis-trans isomerase. We further explored the interaction interface between Atg101 and Fkh1 and found that the WF finger is required for the interaction in vitro. Although the S. cerevisiae Fkh1 homologue, FKBP12, interacts with rapamycin; Fkh1 it is not thought to be directly involved in autophagy. Collectively, our results give new insights into an Atg101-containing Atg1/ULK1 complex and reveals that Atg101’s function may span beyond autophagy.
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Post-translational modification of histones, such as the addition of acetyl groups, is a major regulatory mechanism for gene expression. Histone acetylation is catalyzed by highly conserved lysine acetyltransferase (KAT) enzymes that are often part of large, modular, and multifunctional complexes. Despite their fundamental importance, the reasons behind the tendency of these enzymes to form large complexes remain unclear. We investigated the organization of these complexes by elucidating the molecular architecture of three yeast KAT complexes: Spt-Ada-Gcn5 Acetyltransferase (SAGA), nucleosomal acetyltransferase of histone H4 (NuA4), and Elongator. The yeast SAGA complex is the largest KAT complex in yeast, and activates the expression of many stress response genes. Mutations of its human homologues have been implicated in spinocerebellar ataxia and oncogenesis. Using single particle electron microscopy and crosslinking coupled to mass spectrometry, we show that the catalytic module of SAGA resides within a highly flexible tail adjacent to numerous chromatin-binding subunits. We propose that the flexible SAGA tail is the nucleosome-interacting surface, and its plasticity serves to accommodate the various configurations of the chromatin substrate. NuA4 is another KAT complex whose catalytic subunit, Esa1, is the only essential KAT in yeast. NuA4 has highly conserved roles in the expression of housekeeping genes and the DNA damage repair pathway. Its subunits organize into modules that act independently of the complex. We show that these moonlighting modules form distinct globular structures that are peripherally associated with NuA4, which likely facilitates their dynamic nature. Similar to SAGA, NuA4 subunits that bind chromatin surrounds its catalytic subunit, possibly positioning its substrate nucleosome for efficient acetylation. Yeast Elongator, consisting of two copies each of six unique subunits, was initially characterized as a component of the elongating RNA polymerase II holoenzyme with histone acetyltransferase activity. However, further research has revealed a prominent role for the complex in modifying the wobble base pair of tRNAs. We generated the first three-dimensional reconstruction of Elongator and show that it organizes asymmetrically, with the two copies of its catalytic subunit residing in very different environments. Our structural investigations represent the first steps towards understanding the molecular mechanisms of these enigmatic complexes.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Transcription initiation is a major regulatory step in eukaryotic gene expression. Packaging of DNA into chromatin serves as a barrier against transcription, thus various chromatin modifiers are required to make chromatin structure less compact and more accessible for transcriptional machinery. Spt-Ada-Gcn5-Acetyltansferase (SAGA) is a conserved multi-subunit complex that activates RNA polymerase II-mediated transcription by acetylating and deubiquitinating nucleosomal histones and by recruiting TATA box binding protein (TBP) to DNA. The prototypical yeast Saccharomyces cerevisiae SAGA contains 19 subunits that are organized into Tra1, core, histone acetyltransferase, and deubiquitination modules. Advances in cryo-EM technologies have enabled the determination of the high-resolution structures of the large Tra1 subunit and, more recently, the Tra1 and the core modules in the context of full yeast SAGA. However, the two catalytical modules were poorly resolved due to conformational flexibility of the full assembly. Furthermore, the high sample requirement created a formidable barrier to structural investigations of SAGA. Here, we report a workflow for preparing high quality SAGA cryo-EM specimens at low protein concentration using a graphene oxide support layer. With this procedure, we were able to determine a cryo-EM reconstruction of yeast SAGA at 3.1 Å resolution and examine its conformational landscape with the neural network-based algorithm cryoDRGN. Our analysis revealed that SAGA adopts a range of conformations with its HAT module and central core in different orientations relative to Tra1.
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In eukaryotes, autophagy is an evolutionarily conserved and essential “self-degradative” process used to maintain cellular homeostasis. Central to autophagy is the formation of double-membrane vesicles termed autophagosomes. The process of autophagosome formation is coordinated by over 35 autophagy-related (Atg) proteins. The Atg1 kinase complex constitutes one group of proteins required for the initial induction step of autophagosome formation. The Atg1 kinase complex is composed of the kinase Atg1, a regulatory phosphoprotein Atg13, and a protein scaffold Atg17 that forms a ternary complex with Atg31 and Atg29. In this study, we have determined the structure of the Saccharomyces cerevisiae Atg17-Atg31-Atg29 ternary complex by single-particle electron microscopy. The complex is an “S-shaped” dimer exhibiting an elongated architecture with an end-to-end distance of 345Å. Atg17 was found to form the central scaffold while Atg31 and Atg29 formed two globular densities tethered to the arcs formed by Atg17. Further analysis of purified Atg17 dimers showed that Atg17 mediated dimerization of the complex while Atg31 and Atg29 had a structural role in maintaining the distinct curvature of the complex. We further studied Atg1 kinase complex assembly by co-expressing a minimal pentameric assembly consisting of Atg1 CTD (residues 589-897) and Atg13 CTD (residues 384-738) with Atg17-Atg31-Atg29. Structural analysis localized Atg1 CTD and Atg13 CTD to the terminal regions of the ternary complex supporting that the N-terminus of Atg17 likely mediates complex assembly. Finally, we structurally characterized an important Atg1 kinase complex interacting partner, Atg11. Purified Atg11 exhibited an elongated architecture supporting its role as a coiled-coil protein scaffold.
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