Dattatreya Mellacheruvu

University of Michigan | U-M · Department of Computational Medicine and Bioinformatics

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the typ...

Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease with mutations in cardiac myosin binding protein C (MYBPC3) being most prevalent. Mechanisms underlying pathogenesis of MYBPC3‐linked HCM remain unclear. >90% of MYBPC3 mutations are nonsense and whether these mutations lead to loss‐ or gain‐of‐function is unresolv...

Epigenetic modifying proteins have been implicated in many forms of cancer including acute myeloid leukemia (AML). The Polymerase Associated Factor complex (PAFc) is an epigenetic regulator complex linked with the deposition of epigenetic modifications associated with transcriptional activation. The PAFc is composed of six subunits in humans‐ PAF1,...

Significance In humans, SEC23B deficiency results in congenital dyserythropoietic anemia type II, a disease of abnormal red blood cell development, while SEC23A deficiency results in cranio-lenticulo-sutural-dysplasia, a disease characterized by bone abnormalities due to defective collagen secretion (but no red blood cell defect). In this study, we...

Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental kn...

The Polymerase Associated Factor 1 complex (PAF1c) is an epigenetic comodifying complex that directly contacts RNA polymerase II (RNAPII) and several epigenetic regulating proteins. Mutations, overexpression and loss of expression of subunits of the PAF1c are observed in various forms of cancer suggesting proper regulation is needed for cellular de...

SEC23 is a core component of the coat protein-complex II (COPII)-coated vesicle, which mediates transport of secretory proteins from the endoplasmic reticulum (ER) to the Golgi ¹⁻³ . Mammals express 2 paralogs for SEC23 (SEC23A and SEC23B). Though the SEC23 gene duplication dates back >500 million years, both SEC23’s are ~85% identical at the amino...

There is a need to better understand and handle the 'dark matter' of proteomics-the vast diversity of post-translational and chemical modifications that are unaccounted in a typical mass spectrometry-based analysis and thus remain unidentified. We present a fragment-ion indexing method, and its implementation in peptide identification tool MSFragge...

Introduction: Myosin binding protein C (MYBPC3) is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM) and >90% of MYBPC3 mutations produce truncated proteins. Ubiquitin proteasome dysfunction has been observed in human HCM hearts with MYBPC3 mutations and in experimental models, but the mechanisms responsible are unknown. We hypo...

Yeast pseudohyphal filamentation is a stress-responsive growth transition relevant to processes required for virulence in pathogenic fungi. Pseudohyphal growth is controlled through a regulatory network encompassing conserved MAPK (Ste20p, Ste11p, Ste7p, Kss1p, and Fus3p), protein kinase A (Tpk2p), Elm1p, and Snf1p kinase pathways; however, the sco...

Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration resistant prostate cancer (CRPC). Substantial prior work has focused on targeting AR directly; however, the identification and therapeutic targeting of co-activators of AR signaling remains an underexplored area of potential cl...

Toward our goal of personalized medicine, we comprehensively profiled pre-treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib-based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially-regulated...

Affinity purification coupled with mass spectrometry (AP-MS) is a high-throughput approach to detect protein interactions, where a protein complex is affinity-purified using an antibody targeted against a clonally modified member of the complex that expresses an epitope tag (bait) and analyzed using protein mass spectrometry. In most cases, co-puri...

The yeast Saccharomyces cerevisiae undergoes a dramatic growth transition from its unicellular form to a filamentous state, marked by the formation of pseudohyphal filaments of elongated and connected cells. Yeast pseudohyphal growth is regulated by signaling pathways responsive to reductions in the availability of nitrogen and glucose, but the mol...

Affinity purification coupled with mass spectrometry (AP-MS) is a widely used approach for the identification of protein-protein interactions. However, for any given protein of interest, determining which of the identified polypeptides represent bona fide interactors versus those that are background contaminants (for example, proteins that interact...

The budding yeast Saccharomyces cerevisiae can respond to nutritional and environmental stress by implementing a morphogenetic program wherein cells elongate and interconnect, forming pseudohyphal filaments. This growth transition has been studied extensively as a model signaling system with similarity to processes of hyphal development that are li...

Significance Analysis of INTeractome (SAINT) is a software package for scoring protein-protein interactions based on label-free quantitative proteomics data (e.g., spectral count or intensity) in affinity purification-mass spectrometry (AP-MS) experiments. SAINT allows bench scientists to select bona fide interactions and remove nonspecific interac...

We present 'significance analysis of interactome' (SAINT), a computational tool that assigns confidence scores to protein-protein interaction data generated using affinity purification-mass spectrometry (AP-MS). The method uses label-free quantitative data and constructs separate distributions for true and false interactions to derive the probabili...

1902 Introduction Multiple myeloma (MM) remains mostly incurable. Novel therapies have improved response rates, which are now reaching 100%. More importantly, number of recent studies showed that the depth of response, e.g. achievement of at least 90% reduction of the disease (≥VGPR) is associated with longer disease control. Therefore, improving...

618 Introduction Despite an increased number of new treatments, multiple myeloma (MM) remains mostly incurable. There is emerging evidence that achieving complete or near complete response (CR/nCR), or at least a 90% reduction of the disease (≥VGPR), in response to initial treatment when MM is most sensitive to chemotherapy is associated with impr...

4034 Introduction Multiple myeloma (MM) is a monoclonal gammopathy characterized by the uncontrolled proliferation of plasma cells (PCs). The lack of knowledge about MM cell biology compared to normal PCs is hindering the discovery of myeloma specific targeted therapeutics. Current therapeutics target broad cellular functions such as suppression o...

Supplementary Figure 1. Literature overlap for the TIP49 dataset using SAINT with and without control purification data.

Supplementary Table 2. Supplementary data for the DUB dataset. 2A) List of all detected interactions and scores from CompPASS and SAINT. 2B–D) GO terms enrichment in top scoring interactions for each scoring method.

Supplementary Table 1. Supplementary data for the TIP49 dataset. 1A) List of all detected interactions and scores from PP-NSAF, CompPASS, and SAINT. 1B) All interactions in control purifications were included in a separate table after merging of 35 technical replicate purifications into 9 purifications. 1C) Table of technical replicates of control...

Supplementary Table 3. Supplementary data for the CDC23 dataset. List of all detected interactions with SAINT scores and results reported by t-test.

4865 Introduction Despite an increased number of new treatments, multiple myeloma (MM) remains mostly incurable. There is emerging evidence that achieving at least 90% disease reduction (very good partial response, VGPR) is associated with improved control of disease (Jakubowiak et al, JCO, in press). However, even with the most active regimens, 4...