Marcos Rodrigo Alborghetti

Brazilian Biosciences National Laboratory

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Jörg Kobarg

Universidade Estadual de Campinas (UNICAMP)

Adriana Franco Paes Leme

Laboratório Nacional de Ciência e Tecnologia do Bioetanol

Maurício L. Sforça

Brazilian Center for Research in Energy and Materials

Kleber G. Franchini

Instituto Dante Pazzanese de Cardiologia

Ana Carolina de Mattos Zeri

Brazilian Biosciences National Laboratory

Carlos Eduardo Leite Arieta

Universidade Estadual de Campinas (UNICAMP)

Daniel Borges

Universidade Estadual de Campinas (UNICAMP)

Maria Elvira Pizzigatti Corrêa

Universidade Estadual de Campinas (UNICAMP)

Marília Trindade Ferrer

Universidade Estadual de Campinas (UNICAMP)

Ana Cláudia Viana Wanzeler

Universidade Estadual de Campinas (UNICAMP)

Cooperative Institutions

Universidade Estadual de Campinas (UNICAMP)

106

Brazilian Biosciences National Laboratory

Universidade de São Paulo

Brazilian Center for Research in Energy and Materials

Laboratório Nacional de Ciência e Tecnologia do Bioetanol

Brazilian Synchrotron Light Laboratory

Hospital de Clínicas da Unicamp

Universidade de Brasília

Pontifícia Universidade Católica de Campinas

Universidade Federal de São Carlos

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Abstract 15141: Machine Learning-Driven Serum Metabolomics: Insights Into the Transition to Early-Stage Heart Failure With Preserved Ejection Fraction

Circulation (2022)

Marcos Rodrigo Alborghetti Renato A. Hortegal Jose Pereira Mariana Grizante Renato Cancellier

Introduction: Metabolomics has emerged as a powerful tool in providing readouts of early disease states before clinical manifestation. Here we used the predictive power of Unsupervised Hierarchical Clustering Analysis (UHCA) and Automated Machine Learning (AutoML) algorithms to identify serum metabolic panels in a population at risk of developing HFpEF. Methods: We studied 215 subjects staged as non-HF, pre-HFpEF and early-stage HFpEF(es-HFpEF). We evaluated clinical, laboratory, echocardiographic, and NMR-based metabolomics of blood serum data. UHCA and AutoML were used to explore metabolic fingerprints potentially related to clinical features or HFpEF. We used Metabolite Set Enrichment Analysis to explore biochemical pathways. Results: The UHCA identified three major patients (P) and two metabolites (M) clusters (Figure). The P clusters were associated with HFpEF stages, cardiac remodeling, diastolic dysfunction, and sex (Pearson Chi-square, p < 0.05) and M clusters with glycine and serine metabolism and urea cycle pathways (FDR-adjusted p-value < 0.002). Considering non-HFpEF and es-HFpEF groups, AUROC mean for feature subset combinations was 0.897 and the highest AUROC (0.995) combined metabolites, clinical, laboratory and echo features. Of the 64 models trained that included metabolites as input, serine (25), uridine (17), 2-oxoglutarate (14), citrate (14), 2-aminobutyrate (13) and taurine (13) were observed more frequently with feature importance value greater than zero. The metabolites with higher sum values of feature importance were serine (0.173), uridine (0.131), 2-aminobutyrate (0.123), choline (0.098) and dimethylamine (0.087). Conclusions: This study revealed characteristic metabolite profiles in the sera of patients at risk of developing HFpEF. These metabolite panels can add information for classificatory algorithms development and contribute to the understanding of HFpEF pathophysiology.

False Discovery Rate

10.1161/circ.146.suppl_1.15141

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Fasciculation and elongation zeta proteins 1 and 2: From structural flexibility to functional diversity

World Journal of Biological Chemistry (2019)

Mariana Bertini Teixeira Marcos Rodrigo Alborghetti Jörg Kobarg

Fasciculation and elongation zeta/zygin (FEZ) proteins are a family of hub proteins and share many characteristics like high connectivity in interaction networks, they are involved in several cellular processes, evolve slowly and in general have intrinsically disordered regions.In 1985, unc-76 gene was firstly described and involved in axonal growth in C. elegans, and in 1997 Bloom and Horvitz enrolled also the human homologues genes, FEZ1 and FEZ2, in this process.While nematodes possess one gene (unc-76), mammalians have one more copy (FEZ1 and FEZ2).Several animal models have been used to study FEZ family functions like: C. elegans, D. melanogaster, R. novergicus and human cells.Complementation assays were performed and demonstrated the function conservation between paralogues.Human FEZ1 protein is more studied followed by UNC-76 and FEZ2 proteins, respectively.While FEZ1 and UNC-76 shared interaction partners, FEZ2 evolved and increased the number of protein-protein interactions (PPI) with cytoplasmatic partners.FEZ proteins are implicated in intracellular transport, acting as bivalent cargo transport adaptors in kinesinmediated movement.Especially in light of this cellular function, this family of proteins has been involved in several processes like neuronal development, neurological disorders, viral infection and autophagy.However, nuclear functions of FEZ proteins have been explored as well, due to high content of PPI with nuclear proteins, correlating FEZ1 expression to Sox2 and Hoxb4 gene regulation and retinoic acid signaling.These recent findings open new avenue to study FEZ proteins functions and its involvement in already described processes.This review intends to reunite aspects of evolution, structure, interaction partners and function of FEZ proteins and correlate them to physiological and pathological processes.

Protein family

10.4331/wjbc.v10.i2.28

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Abstract Mo104: Cardiolipin-Metabolite Crosstalk in HFpEF

Circulation Research (2024)

Ali Kamiar Monique Williams Jose Manuel Condor Emely Robleto Anna Kovilakath

Background: Transition from fatty acid oxidation to glycolysis is linked to oncometabolism and cardiac hypertrophy. We hypothesize that such a metabolic shift is pivotal in driving HFpEF in 3 murine models. The citric acid cycle (CAC) enzyme αKGDH is dysregulated in HFpEF patient biopsies and Alport hearts. Therefore, we also hypothesize more generalized CAC dysregulation at αKGDH associated with HFpEF. Methods & Results: Alport and LDLR/P407 mice were generated on 129J background, and HFD/L-NAME HFpEF on C57Bl6N, (n= 5M,5F/group). Two groups of Alport and LDLR/P407 mice were fed a 2% αKG diet, and a 3rd subgroup of Alport mice injected with AAV9-CMV-αKGDH. PET-CT of 18 F-FDG showed significant increased cardiac glucose uptake in Alport and LDLR/P407 mice up to 8 wk of treatment. αKG diet conferred significantly increased cardiac glucose uptake and worse diastolic dysfunction in LDLR/P407 mice. αKGDH protein expression was reduced by ~40% (p<.05) in the HFD/L-NAME hearts. Targeted metabolomic analysis by LC-MS/MS indicated normalization of intermediate metabolites in LDLR/P407 hearts by αKG diet and significantly shortening life spans (p<.001). The αKG diet exacerbated adverse remodeling of cardiolipin (CL) in LDLR/P407 hearts. Expression of CL remodeling enzymes, CL Synthase (p<.05) and Tafazzin (p<.0001), were altered in the LDLR/P407 hearts. NADH increased in Alport and LDLR/P407 hearts suggesting decreased ATP availability and impaired oxidative phosphorylation. HFD/L-NAME HFpEF mice showed a possible block in CAC flux at αKGDH, with increased αKG and reduced succinyl-CoA. Acetyl-CoA and αKG were increased in Alport hearts. Serum metabolic signatures in 273 patients by 1 H NMR stratified into non-HF, pre-HFpEF, and HFpEF by the H2FPEF algorithm, indicated elevated serum αKG levels associated with patients with higher H2FPEF scores. Leucine is increased in LDLR/P407 and HFD/L-NAME hearts consistent with published findings in patients with HFpEF. These 2 models also have increased levels of purines. Increased G-6P in LDLR/P407 hearts supports increased glucose uptake. Glutamine is increased in HFD/L-NAME, consistent with published findings in patients with HFpEF. Conclusions: Dysregulated αKG and CL remodeling modulate oncometabolism and energy transduction that exacerbate HF in Alport, LDLR/P407, and HFD/L-NAME mice. Circulating αKG may constitute a marker of CAC dysfunction in HFpEF patients and αKGHD activation as a potential therapeutic goal.

Crosstalk

10.1161/res.135.suppl_1.mo104

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FEZ2 Has Acquired Additional Protein Interaction Partners Relative to FEZ1: Functional and Evolutionary Implications

PLoS ONE (2011)

Marcos Rodrigo Alborghetti Ariane Silva Furlan Jörg Kobarg

Background The FEZ (fasciculation and elongation protein zeta) family designation was purposed by Bloom and Horvitz by genetic analysis of C. elegans unc-76. Similar human sequences were identified in the expressed sequence tag database as FEZ1 and FEZ2. The unc-76 function is necessary for normal axon fasciculation and is required for axon-axon interactions. Indeed, the loss of UNC-76 function results in defects in axonal transport. The human FEZ1 protein has been shown to rescue defects caused by unc-76 mutations in nematodes, indicating that both UNC-76 and FEZ1 are evolutionarily conserved in their function. Until today, little is known about FEZ2 protein function. Methodology/Principal Findings Using the yeast two-hybrid system we demonstrate here conserved evolutionary features among orthologs and non-conserved features between paralogs of the FEZ family of proteins, by comparing the interactome profiles of the C-terminals of human FEZ1, FEZ2 and UNC-76 from C. elegans. Furthermore, we correlate our data with an analysis of the molecular evolution of the FEZ protein family in the animal kingdom. Conclusions/Significance We found that FEZ2 interacted with 59 proteins and that of these only 40 interacted with FEZ1. Of the 40 FEZ1 interacting proteins, 36 (90%), also interacted with UNC-76 and none of the 19 FEZ2 specific proteins interacted with FEZ1 or UNC-76. This together with the duplication of unc-76 gene in the ancestral line of chordates suggests that FEZ2 is in the process of acquiring new additional functions. The results provide also an explanation for the dramatic difference between C. elegans and D. melanogaster unc-76 mutants on one hand, which cause serious defects in the nervous system, and the mouse FEZ1 -/- knockout mice on the other, which show no morphological and no strong behavioural phenotype. Likely, the ubiquitously expressed FEZ2 can completely compensate the lack of neuronal FEZ1, since it can interact with all FEZ1 interacting proteins and additional 19 proteins.

Fasciculation

Interactome

Functional divergence

Protein family

10.1371/journal.pone.0017426

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A Draft of the Human Septin Interactome

PLoS ONE (2010)

Marcel Nakahira Joci Neuby Alves Macêdo Thiago Vargas Seraphim Nayara S. Cavalcante T.A.C.B. Souza

Septins belong to the GTPase superclass of proteins and have been functionally implicated in cytokinesis and the maintenance of cellular morphology. They are found in all eukaryotes, except in plants. In mammals, 14 septins have been described that can be divided into four groups. It has been shown that mammalian septins can engage in homo- and heterooligomeric assemblies, in the form of filaments, which have as a basic unit a hetero-trimeric core. In addition, it has been speculated that the septin filaments may serve as scaffolds for the recruitment of additional proteins.Here, we performed yeast two-hybrid screens with human septins 1-10, which include representatives of all four septin groups. Among the interactors detected, we found predominantly other septins, confirming the tendency of septins to engage in the formation of homo- and heteropolymeric filaments.If we take as reference the reported arrangement of the septins 2, 6 and 7 within the heterofilament, (7-6-2-2-6-7), we note that the majority of the observed interactions respect the "group rule", i.e. members of the same group (e.g. 6, 8, 10 and 11) can replace each other in the specific position along the heterofilament. Septins of the SEPT6 group preferentially interacted with septins of the SEPT2 group (p<0.001), SEPT3 group (p<0.001) and SEPT7 group (p<0.001). SEPT2 type septins preferentially interacted with septins of the SEPT6 group (p<0.001) aside from being the only septin group which interacted with members of its own group. Finally, septins of the SEPT3 group interacted preferentially with septins of the SEPT7 group (p<0.001). Furthermore, we found non-septin interactors which can be functionally attributed to a variety of different cellular activities, including: ubiquitin/sumoylation cycles, microtubular transport and motor activities, cell division and the cell cycle, cell motility, protein phosphorylation/signaling, endocytosis, and apoptosis.

Septin

10.1371/journal.pone.0013799

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Additional file 3 of Tear proteomic profile in three distinct ocular surface diseases: keratoconus, pterygium, and dry eye related to graft-versus-host disease

Figshare (2020)

Daniel Borges Marcos Rodrigo Alborghetti Adriana Franco Paes Leme Romênia R. Domingues Bruna Aparecida Rodrigues Duarte

Additional file 3: Table S3. Proteins identified in GVHD and control group tears. Gene names, protein names and ID, and Student´s t-test results comparing all proteins identified in GVHD and control group.

Pterygium

Corneal Diseases

10.6084/m9.figshare.13346376

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The molecular motor Myosin Va interacts with the cilia-centrosomal protein RPGRIP1L

Scientific Reports (2017)

Leandro H. P. Assis Rui Milton Patrício da Silva-Júnior Luciano G. Dolce Marcos Rodrigo Alborghetti Rodrigo V. Honorato

Abstract Myosin Va (MyoVa) is an actin-based molecular motor abundantly found at the centrosome. However, the role of MyoVa at this organelle has been elusive due to the lack of evidence on interacting partners or functional data. Herein, we combined yeast two-hybrid screen, biochemical studies and cellular assays to demonstrate that MyoVa interacts with RPGRIP1L, a cilia-centrosomal protein that controls ciliary signaling and positioning. MyoVa binds to the C2 domains of RPGRIP1L via residues located near or in the Rab11a-binding site, a conserved site in the globular tail domain (GTD) from class V myosins. According to proximity ligation assays, MyoVa and RPGRIP1L can interact near the cilium base in ciliated RPE cells. Furthermore, we showed that RPE cells expressing dominant-negative constructs of MyoVa are mostly unciliated, providing the first experimental evidence about a possible link between this molecular motor and cilia-related processes.

Molecular motor

10.1038/srep43692

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Citations (38)

Fasciculation and elongation zeta‐1 protein (FEZ1) interacts with the retinoic acid receptor and participates in transcriptional regulation of the Hoxb4 gene

FEBS Open Bio (2017)

Mariana Bertini Teixeira Ana Carolina Migliorini Figueira Ariane Silva Furlan Bruno Aquino Marcos Rodrigo Alborghetti

Fasciculation and elongation zeta-1 (FEZ1) protein is involved in axon outgrowth and is highly expressed in the brain. It has multiple interaction partners, with functions varying from the regulation of neuronal development and intracellular transport mechanisms to transcription regulation. One of its interactors is retinoic acid receptor (RAR), which is activated by retinoic acid and controls many target genes and physiological process. Based on previous evidence suggesting a possible nuclear role for FEZ1, we wanted to deepen our understanding of this function by addressing the FEZ1-RAR interaction. We performed in vitro binding experiments and assessed the interface of interaction between both proteins. We found that FEZ1-RAR interacted with a similar magnitude as RAR to its responsive element DR5 and that the interaction occurred in the coiled-coil region of FEZ1 and in the ligand-binding domain of RAR. Furthermore, cellular experiments were performed in order to confirm the interaction and screen for induced target genes from an 86-gene panel. The analysis of gene expression showed that only in the presence of retinoic acid did FEZ1 induce hoxb4 gene expression. This finding is consistent with data from the literature showing the hoxb4 gene functionally involved in development and acute myeloid leukemia, as is FEZ1.

10.1002/2211-5463.12338

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FEZ1 Dimerization and Interaction with Transcription Regulatory Proteins Involves Its Coiled-coil Region

Journal of Biological Chemistry (2006)

Eliana M. Assmann Marcos Rodrigo Alborghetti María Eugenia Camargo Jörg Kobarg

Ankyrin repeat

10.1074/jbc.m513280200

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Citations (53)

Structural and evolutionary insights in fasciculation and elongation zeta (FEZ) proteins family

The FASEB Journal (2011)

Marcos Rodrigo Alborghetti Ariane da Silva Furlan Júlio César da Silva Maurício L. Sforça Jorge Luiz Neves

The human proteins FEZ1 and FEZ2 are orthologs of UNC‐76 from C. elegans , involved in growth and fasciculation of axons. Our aim is to exploit the molecular evolution of the FEZ protein family with emphasis on vertebrata branch. By the interactome profile of FEZ1 and FEZ2 from H. sapiens and UNC‐76 from C. elegans we observed a conserved pattern of protein‐protein interactions among FEZ1 and UNC‐76 that explain the ability of FEZ1 to rescue defects caused by unc‐76 mutations in nematodes. Furthermore, we characterized the interaction between FEZ1 and SCOCO (short coiled coil protein) by SAXS (Small Angle X‐ray Scattering). This interaction has been previously reported between their orthologs UNC‐76 and UNC‐69 that cooperate in axonal outgrowth. A hetero‐tetrameric state was observed, which consists of two GST‐SCOCO molecules attached to two FEZ1 molecules. By PAGE, SAXS, MS and NMR we defined that FEZ1 dimerizes by disulfide bond. In vivo this dimeric state could be important for kinesin mediated transport along microtubules. Thereby, FEZ1 may be classified as a dimeric and bivalent transport adaptor, essential to axon outgrowth and normal pre‐synaptic organization and transport of cargoes. The aggregation of new interaction partners found for the FEZ2 protein could be interpreted as the acquisition of new molecular functions and may have occurred in the early stages of chordate evolution. Supported by FAPESP, CNPq.

Fasciculation

10.1096/fasebj.25.1_supplement.lb92

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