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    Experimental Pathology
    105-E Whitehead Bldg., 615 Michael Street
    Atlanta, GA 30322
    404 727-5953 Phone

    For an expert Pathology consultation,
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    1-404-712-5947


    Guy M Benian, MD

    Muscle Cell Biology

    Professor
    Pathology & Laboratory Medicine


    Pathology Faculty Photo

    Other Appointments/Positions

    Professor, Department of Cell Biology, Emory University


    Pathology Division(s):
    Experimental Pathology


    Email Address:
    pathgb@emory.edu


    Education:

    B.S.   University of Michigan, Ann Arbor, MI, high honors & high distinction, - 1976

    M.D.   Wayne State University School of Medicine, Detroit, MI, - 1980

    Resident   Laboratory Medicine, Barnes Hospital and Washington University, St. Louis, MO, 1980 - 1985

    Postdoc Fellow   Department of Genetics, Washington University, St. Louis, MO, supervisor R.H Waterston, 1981 - 1986



    Research Interests:

    - Using C. elegans to study the assembly and maintenance of the sarcomere
    The sarcomere performs the work of muscle contraction and is a "nano"-machine consisting of a highly ordered assemblage of at least several hundred proteins. Despite ever increasing knowledge of the components and functions of sarcomeric proteins (indeed new ones are discovered each year!), we still don't understand how sarcomeres are assembled, and maintained in the face of muscle contraction. Our lab is studying these questions in the model genetic organism, C. elegans. C. elegans is a superb platform for discovery of new and conserved sarcomeric components, and for learning new information about already known components. We are focused on two questions: (1) What are the structures and functions of the giant muscle proteins (>700,000 Da)? (2) What are the molecular mechanisms by which sarcomeres are attached to the muscle cell membrane and transmit force? Our approaches involve genetics, cell biology and biochemistry. Our studies benefit from collaborations with structural biologists, biophysicists and biomedical engineers. Our studies have relevance for understanding the molecular mechanisms of human inherited diseases of skeletal and heart muscle, including muscular dystrophies, myopathies and cardiomyopathies. The giant muscle proteins consist primarily of multiple copies of immunoglobulin (Ig) and fibronectin type 3 (Fn3) domains, and one or even two protein kinase domains. In C. elegans, there are 3 such proteins, twitchin (754,000 Da, located in the sarcomeric A-band, and one function likely to be regulation of muscle relaxation), TTN-1 (2.2 MDa, located in the I-band and perhaps acting as a molecular spring), and UNC-89 (up to 900,000 Da, a homolog of the human protein obscurin, and having a role in the assembly/maintenance of the M-line). One aim is determining the identity of proteins that interact with these giants that explains their localization and their functions. Other goals including learning the substrates of the protein kinase domains, and to understand how the normally"autoinhibited" kinase domains become activated (in collaboration with Dr. Olga Mayans, University of Konstanz, Germany and Dr. Hang Lu, Georgia Tech.). By cloning mutationally-defined genes, conducting 2-hybrid screens, and localizing proteins with antibodies and GFP fusions, we are defining complex protein interaction networks at muscle attachment sites. We are testing the hypothesis that proteins at the attachment sites are involved in transmitting the force of muscle contraction to the outside of the cell. One project is to understand the molecular mechanism by which one of these proteins, UNC-112 (kindlin in humans), becomes localized to muscle attachment sites. Finally, in collaboration with Dr. Andres Oberhauser (UTMB), we are beginning to study the mechanism by which the conserved protein UNC-45 acts as a chaperone for the folding of the myosin head domain, and how UNC-45 may also repair damaged myosin heads in already established sarcomeres. We are very grateful for grant support from the Human Frontier Science Program and the NIH.



    Honors / Awards:

    Outstanding Service Award, Emorys Graduate Program in Genetics and Molecular Biology, 2005-2006

    Established Investigator Award, American Heart Association, 1991-1996

    Muscular Dystrophy Association Postdoctoral Fellow, 1982 & 1983

    B.S. w/ high honors, University of Michigan, 1976

    Selected Publications:

    Published and Accepted Research Articles -

    Loveless T, Qadota H, Benian GM, Hardin J. C. elegans SORB-1 localizes to integrin adhesion sites and is required for organization of sarcomeres and mitochondria in myocytes. Mol. Biol. Cell, in press (chosen by editors for cover art)


    Qadota H, Matsunaga Y, Nguyen K, Mattheyses A, Hall DH, Benian GM. High resolution imaging of muscle attachment structures in C. elegans, Cytoskeleton 74: 426-442, 2017 (chosen by editors for cover art)


    Sonowal R, Swimm A, Sahoo A, Luo L, Matsunaga Y, Wu Z, Bhingarde JA, Ejzak EA, Ranawade A, Qadota H, Powell DN, Capaldo CT, Flacker JM, Jones RM, Benian GM, Kalman D. Indoles from commensal bacteria extend healthspan. Proc Natl Acad Sci U S A. 2017 Aug 21. pii: 201706464. doi: 10.1073/pnas.1706464114. [Epub ahead of print]


    Yohei Matsunaga, Hyundoo Hwang, Barbara Franke, Rhys Williams, McKenna Penley, Hiroshi Qadota, Hong Yi, Levi T. Morran, Hang Lu, Olga Mayans, and Guy M. Benian. Twitchin kinase inhibits muscle activity. Mol. Biol. Cell 28, 1591-1600, 2017


    Hwang H, Barnes DE, Matsunaga Y, Benian GM, Ono S, and Lu H (2016). Muscle contraction phenotypic analysis enabled by optogenetics reveals functional relationships of sarcomere components in Caenorhabditis elegans. Scientific Reports, 6:19900, DOI: 10.1038/srep19900


    Gieseler K, Qadota H, Benian GM: Development, structure and maintenance of C. elegans body wall muscle (August 23, 2016), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.81.2, http://www.wormbook.org


    Hiroshi Qadota, Olga Mayans, Yohei Matsunaga, Jonathan L. McMurry, Kristy J. Wilson, Grace E. Kwon, Rachel Stanford, Kevin Deehan, Tina L. Tinley, Verra M. Ngwa and Guy M. Benian (2016).The SH3 domain of UNC-89 (obscurin) interacts with paramyosin, a coiled-coil protein, in C. elegans muscle. Mol. Biol. Cell 27: 1606-1620.


    Matsunaga Y, Honda Y, Honda S, Iwasaki T, Qadota H, Benian GM, Kawano T. Diapause is assoicated with a change in the polarity of secretion of insulin-like peptides. Nature Comm. 7:10573 DOI: 10.1038/ncomms10573


    Matsunaga Y, Qadota H, Furukawa M, Choe H, Benian GM. Twitchin kinase interacts with MAPKAP kinase 2 in C. elegans striated muscle. Mol. Biol. Cell. 26: 2096-2111 (2015).


    Hwang H, Krajniak J, Matsunaga Y, Benian GM, Lu H. On-demand optical immobilization of Caenorhabditis elegans for high-resolution imaging and microinjection. Lab on a Chip, 2014, in press


    Qadota H, and Benian GM. An approach for exploring interaction between two proteins in vivo (a review). Frontiers in Physiol. April 2014, volume 5, article 162


    Qadota H, Luo Y, Matsunaga Y, Park AS, Gernert KM, Benian GM: Suppressor mutations suggest a surface on PAT-4 (ILK) that interacts with UNC-112 (Kindlin), J. Biol. Chem. 289, 14252-14262, 2014


    Bommarius B, Anyanful A, Izrayelit Y, Bhatt S, Cartwright E, Benian GM, Schroeder F, and Kalman D: A family of indoles regulate virulence of pathogenic E. coli, PLoS ONE 8(1), e54456, 2013.


    Warner A, Xiong G, Qadota H, Rogalski T, Vogl AW, Moerman DG, and Benian GM: CPNA-1, a copine domain protein, is located at integrin adhesion sites, and is required for myofilament stability in C. elegans, Mol. Biol. Cell 24: 601-616, 2013.


    Lecroisey C, Brouilly N, Qadota H, Mariol MC, Rochette NC, Martin E, Benian GM, Segalat L, Mounier N, Gieseler K: ZYX-1, the unique zyxin protein of C. elegans, is involved in dystrophin-dependent muscle degeneration, Mol. Biol. Cell. 24: 1232-1249, 2013


    Mayans O, Benian GM, Simkovic F, and Rigden DJ. (invited review) Mechanistic and functional diversity in the mechanosensory kinases of the titin-like family. Biochem. Soc. Trans. 41, 1066-1071, 2013.


    Wilson K.J., Qadota H., Mains P., and Benian G.M. UNC-89 (obscurin) binds to MEL-26, a BTB domain protein, and affects the function of MEI-1 (katanin) in striated muscle of C. elegans, Mol. Biol. Cell 23: 2623-2634, 2012.


    von Castelmur E, Strümpfer J, Franke B, Bogomolovas J, Barbieri S, Qadota H, Konarev PV, Svergun DI, Labeit S, Benian GM, Schulten K, and Mayans O: Identification of an N-terminal inhibitory region as the primary mechanosensory regulator of twitchin kinase. Proc. Nat. Acad. Sci. USA 109: 13608-13613, 2012.


    Qadota H, Moerman DG, and Benian GM: A molecular mechanism for the requirement of PAT-4 (ILK) for the localization of UNC-112 (kindlin) to integrin adhesion sites. J. Biol. Chem. 287: 28537-28551, 2012


    Epstein HF, and Benian GM: Invited Review: Paradigm shifts in cardiovascular research from C. elegans muscle, Trends Cardiovas. Med. 22: 201-209, 2012.


    Spooner PM, Bonner J, Maricq AV, Benian GM, and Norman KR: Large isoforms of UNC-89 (obscurin) are required for muscle cell architecture and optimal calcium release in Caenorhabditis elegans. PLoS ONE 7(7): e40182, 2012.


    Nahabedian, J.F., Qadota, H., Stirman, J.N., Lu, H., and Benian, G.M. Bending amplitude--a new quantitative assay of C. elegans locomotion: identification of phenotypes for mutants in genes encoding muscle focal adhesion components. Methods 56, 95-102, 2012.


    Qadota, H., Miyauchi, T., Nahabedian, J.F., Stirman, J.N., Lu, H., Amano, M., Benian, G.M., and Kaibuchi (2011). PKN-1, a homolog of mammalian PKN, is involved in the regulation of muscle contraction and force transmission in C. elegans. J. Mol. Biol. 407, 222-231.


    Warner, A., Qadota, H., Benian, G.M., Vogl, A.W., and Moerman, D.G. The C. elegans paxillin ortholog, PXL-1, is required for pharyngeal muscle contraction and for viability. Mol. Biol. Cell 22: 2551-2563, 2011.


    Benian, GM, and Epstein, HF. Caenorhabditis elegans muscle:a genetic and molecular model for protein interactions in the heart (invited review). Circulation Research 109: 1082-1095, 2011.


    Forbes JG, Flaherty DB, Ma K, Qadota H, Benian GM, Wang K. Extensive and modular intrinsically disordered segments in C. elegans TTN-1 and implications in filament binding, elasticity and oblique striation. J. Mol. Biol. 398: 672-689, 2010


    Moulder, GL, Cremona, GH, Duerr, J., Stirman, JN, Fields, SD, Martin, W, Qadota, H, Benian, GM, Lu, H, and Barstead, RJ: ±-actinin is required for proper assembly of Z-disk / focal adhesion-like structures and for efficient locomotion in C. elegans, J. Mol. Biol. 403: 516-528, 2010.


    Xiong G, Qadota H, Mercer, KB, McGaha LA, Oberhauser AF, Benian GM: A LIM-9 (FHL) / SCPL-1 (SCP) complex interacts with the C-terminal protein kinase regions of UNC-89 (obscurin) in C. elegans muscle. J. Mol. Biol. 386: 976-988, 2009.


    Mercer KB, Szlam S, Walthall W, Benian GM, Gutekunst C-A: C. elegans homolog of Huntington-associated protein 1 and Milton is expressed in chemosensory neurons and in a number of other somatic cell types. J. Mol. Neurosci. 37: 37-49, 2009.


    Anyanful A, Easley KA, Benian GM, Kalman D: Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli by activating genes that regulate lifespan and innate immunity. Cell Host & Microbe 5: 450-462, 2009.


    Miller RK, Qadota H, Stark TJ, Mercer KB, Wortham TS, Anyanful A, Benian GM: CSN-5, a component of the COP9 signalosome complex, regulates the levels of UNC-96 and UNC-98, two components of M-lines in C. elegans muscle. Mol. Biol. Cell. 20: 3608-3616, 2009.


    Qadota H, McGaha LA, Mercer KB, Stark TJ, Ferrara TM, Benian GM: A novel protein phosphatase is a binding partner for the protein kinase domains of UNC-89 (obscurin) in C. elegans. Mol. Biol. Cell. 19: 2424-2432, 2008.


    Greene DN, Garcia T, Sutton RB, Gernert KM, Benian GM, Oberhauser AF: Single-molecule force spectroscopy reveals a stepwise unfolding of C. elegans giant protein kinase domains. Biophys. J. 95: 1360-1370, 2008. (chosen by editors for cover art).


    Miller RK, Qadota H, Mercer KB, Gernert KM, Benian GM: UNC-98 and UNC-96 interact with paramyosin to promote its incorporation into thick filaments of C. elegans. Mol. Biol. Cell. 19: 1529-1539, 2008.


    Qadota H, Blangy A, Xiong G, Benian GM: The DH / PH region of the giant protein UNC-89 activates RHO-1 GTPase in C. elegans body wall muscle. J. Mol. Biol. 383: 747-752, 2008.


    Qadota H, Mercer KB, Miller RK, Kaibuchi K, Benian GM: Two LIM domain proteins and UNC-96 link UNC-97/PINCH to myosin thick filaments in C. elegans muscle. Mol. Biol. Cell. 18: 4317-4326, 2007.


    Stevenson TO, Mercer KB, Cox EA, Szewczyk NJ, Conley CA, Hardin JD, Benian GM: unc-94 encodes a tropomodulin in C. elegans. J. Mol. Biol. 374: 936-950, 2007


    Miller RK, Qadota H, Landsverk M, Mercer KB, Epstein HF, and Benian GM: UNC-98 links an integrin-associated complex to thick filaments in C. elegans muscle (Report). J. Cell Biol. 175: 853-859, 2006


    Mercer, KB, Miller, RK, Tinley, TL, Sheth, S, Qadota, H, Benian, GM: C. elegans UNC-96 is a new component of M-lines that interacts with UNC-98 and paramyosin and is required in adult muscle for assembly and/or maintenance of thick filaments. Mol. Biol. Cell 17: 3832-3847, 2006.


    Zastrow, MS, Flaherty, DB, Benian, GM, Wilson, KL: Nuclear titin interacts with A- and B-type lamins in vitro and in vivo, J. Cell Sci. 119: 239-249, 2006.


    Ayanaful, A, Dolan-Livengood, JM, Lewis, T, Sheth, S, DeZalia, Sherman, MA, MN, Kalman, LV, Benian, GM, Kalman, D: Paralysis and killing of C. elegans by enteropathogenic E. coli requires the bacterial tryptophanase gene, Mol. Microbiol. 57(4): 988-1007, 2005


    Small, TM, Gernert KM, Flaherty DB, Mercer KB, Borodovsky M, Benian GM: Three new isoforms of C. elegans UNC-89 containing MLCK-like protein kinase domains. J. Mol. Biol.342: 91-108, 2004


    Ono K, Parast M, Alberico C, Benian GM, and Ono S: Specific requirements of two ADF/cofilin isoforms in distinct actin-dependent processes in C. elegans. J. Cell Sci. 116: 2073-2085, 2003


    Mercer KB, Flaherty DB, Miller RK, Qadota H, Tinley TL, Moerman DG, and Benian GM: C. elegans UNC-98, a C2H2 Zn finger protein, is a novel partner of UNC-97 / PINCH in muscle adhesion complexes. Mol. Biol Cell 14: 2492-2507, 2003.


    Flaherty DB, Gernert KM, Shmeleva N, Tang X, Mercer KB, Borodovsky M, and Benian GM: Titins in C. elegans with unusual features: coiled-coil domains, novel regulation of kinase activity and two new possible elastic regions. J. Mol. Biol. 323(3): 533-549, 2002


    Ono S, McGough A, Pope BJ, Tolbert VT, Bui A, Pohl J, Benian GM, Gernert KM, and Weeds AG. The C-terminal tail of UNC-60B (ADF/cofilin) is critical for maintaining its stable association with F-actin and is implicated in the second actin-binding site, J. Biol. Chem. 276(8):5952-5958, 2001


    Edens WA, Sharling L, Cheng G., Shapira R, Kinkade JM, Lee T, Edens HA, Tang X, Flaherty DB, Benian GM, and Lambeth JD: Tyrosine cross-linking of extracellular matrix is catalyzed by duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox, J. Cell Biol. 154(4): 879 -891, 2001 (chosen by editors for cover art)


    Ono S, Baillie DL and Benian GM: UNC-60B, an ADF/cofilin family protein, is required for proper assembly of actin into myofibrils in C. elegans body wall muscle, J. Cell Biol. 145(3): 491-502, 1999


    Ono S, and Benian GM: Two C. elegans actin depolymerizing factor/cofilin proteins, encoded by the unc-60 gene, differentially regulate actin filament dynamics, J. Biol Chem. 273: 3778-3783, 1998


    Heierhorst J, Kobe B, Feil SC, Parker MW, Benian GM, Weiss KR, and Kemp BE: Ca+2/S100 regulation of giant protein kinases. Nature 380: 636-639, 1996


    Hardman WJ, Benian GM, Howard T, McGowan JE, Metchock B, and Murtagh JJ: Inflammatory necrotizing granulomas that are acid fast stain and culture negative for Mycobacteria but positive by PCR in formalin-fixed paraffin embedded tissue with CP follow-up. Am. J. Clin. Path. 106: 384-389, 1996


    Kobe B, Heierhorst J, Feil SC, Parker MW, Benian GM, Weiss KR, and Kemp BE: Giant protein kinases: domain interactions and structural basis of autoregulation, EMBO J. 24: 6810-6821,1996


    Heierhorst J, Tang X, Lei J, Kemp B, Weiss K, and Benian GM: Substrate requirements, inhibition by naphthylene sulfonates, and distinct calmodulin affinities of twitchin kinases, Eur. J. Biochem. 242: 454-459, 1996


    Benian GM, Tinley TL, Tang X, and Borodovsky M: The C. elegans gene unc-89, required for muscle M-line assembly, encodes a giant modular protein containing Ig & signal transduction domains. J. Cell Biology 132(5): 835-848, 1996


    Fong S, Hammill SJ, Proctor M, Freund SMV, Benian GM, Chothia C, Bycrott M, and Clarke J: Structure and stability of an immunoglobulin superfamily domain from twitchin, a muscle protein of the nematode C. elegans, J. Mol. Biol. 264: 624-639, 1996


    Ayme-Southgate A, Southgate R, Saide JD, Benian GM, and Pardue ML: Both synchronous and asynchronous muscle isoforms of projectin, the Drosophila bent locus product, contain functional kinase domains. J. Cell Biology 128(3):393-403, 1995


    Hu S-H, Parker MW, Lei J, Wilce MCJ, Benian GM and Kemp BE: Intrasteric regulation of protein kinases: insights from the crystal structure of twitchin kinase. Nature 369:581-584, 1994


    Hu S-H, Lei J, Wilce MCJ, Valenzuela MRL, Benian GM, Parker MW, and Kemp BE: Crystallization and preliminary x-ray analysis of the auto-inhibited twitchin kinase. J. Mol. Biol. 236:1259-1261, 1994


    Lei J, Tang X, Chambers T, Pohl J, and Benian GM: The protein kinase domain of twitchin has protein kinase activity and an autoinhibitory region. J. Biol. Chem. 269(33):21078-21085, 1994


    Schein JE, Marra MA, Benian GM, Fields C, and Baillie DL: The use of deficiencies to determine essential gene content in the let-56-unc-22 region of C. elegans. Genome 36:1148-1156, 1993


    L'Hernault SW, Benian GM, and Emmons RB: Genetic and molecular characterization of the Caenorhabditis elegans spermatogenesis defective gene spe-17. Genetics134:769-780, 1993


    Benian GM, L'Hernault SW, and Morris ME, Additional sequence complexity in the muscle gene, unc-22, and its encoded protein, twitchin, of C. elegans. Genetics 134:1097-1104, 1993


    Ayme-Southgate A, Vigoreaux J, Benian G, and Pardue ML: Drosophila has a twitchin/titin-related gene that appears to encode projectin. Proc. Nat. Acad. Sci. USA 88:7973-7977, 1991


    Benian GM, Kiff JE, Neckelmann N, Moerman DG, Waterston RH: The sequence of twitchin: An unusually large protein implicated in regulation of myosin activity in C. elegans. Nature 342:45-50, 1989


    Moerman DG, Benian GM, Barstead RJ, Schriefer L, and Waterston RH: Identification and intracellular localization of the unc-22 gene product of C. elegans. Genes and Development 2:93-105, 1988


    Mori I, Benian GM, Moerman DG, and Waterston RH: The transposon Tcl of C. elegans recognizes specific target sequences for integration. Proc. Nat. Acad. Sci. USA 85:861-864, 1988


    Benian GM and Murray P: Practical modification of conventional blood culture systems for recovery of mycobacteria. Diagn. Microbiol. Infect. Dis. 4:351-353, 1986


    Moerman DG, Benian GM, and Waterston RH: Molecular cloning of the muscle gene unc-22 in C. elegans by Tcl transposon tagging. Proc. Nat. Acad. Sci. USA 83:2579-2583, 1986


    Totty WG, Romano T, Benian GM, Gilula LA, and Sherman LA: Serum sickness following streptokinase therapy - brief report. Am. J. of Roentgenol. 138:143-144, 1982


    Rittenhouse HG, Benian GM, Rittenhouse JW, Hansen ER, and Boyd LE: Heterogeneity of concanavalin A receptors on Ehrlich tumor cells, In: Membranes and Neoplasia: New Approaches and Strategies, Marchessi VT (ed) pp 203-213, 1976


    Other Publications -

    Benian GM and Mayans O. Commentary (invited): Titin and obscurin: giants holding hands and discovery of a new Ig domain subset. J. Mol. Biol. 427: 707-714, 2015.


    Wilson K.J., Qadota H., and Benian G.M. Immunofluorescent localization of proteins in C. elegans muscle. In: Methods in Molecular Biology vol. 798, Myogenesis: Methods and Protocols, J.X. DiMario, ed., Humana Press, 2012.


    Bernstein S.I. and Benian G.M. Guest Editor's Introduction: Introduction to methods in invertebrate muscle biology. Methods 56, 1-2, 2012.


    Qadota H, Benian GM: Molecular structure of sarcomere-to-membrane attachment at M-lines in C. elegans muscle. (Review). J. Biomed. Biotech. volume 2010, article ID 864749, doi:10.1155/2010/864749


    Ferrara TM, Flaherty DB, and Benian GM: Titin / connectin-related proteins in C. elegans: A review and new findings, J. Mus. Res. and Cell Motil. 26: 435-447, 2005.


    Chamberlain JS and Benian GM: Muscular dystrophy: The worm turns to genetic disease, Current Biology 10: R795-R797, 2000.


    Benian GM, Ayme-Southgate A, and Tinley TL: The genetics and molecular biology of titin/connectin-like proteins in invertebrates, Reviews of Physiology, Biochemistry and Pharmacology 138: 235-268, 1999.


    Benian GM, Tang X, and Tinley TL: Twitchin and related giant Ig superfamily members of C. elegans and other invertebrates (In: Muscle Elastic Proteins), Advances in Biophysics 33:183-197, 1996.