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Profile of Ra ´Ul Padr PROFILE Profile of Ra´ul Padr´on PROFILE Jennifer Viegas, Science Writer Over the past four decades, structural biologist Ra ´ul physiology and biophysics, which Padr ´onhas elucidated muscle contraction at the mo- he earned in 1979. His doctoral lecular and atomic level using a model system that he thesis was a study of the structure and his colleague Roger Craig developed: tarantula and function of the myelin sheath skeletal muscle. Padr ´on’s research on how skeletal of toad and frog sciatic nerves muscle thick filaments relax and become activated is and how the nerves respond to helping to inform the molecular pathogenesis of hu- anesthetics (2). man muscle diseases. For such advances, Padr ´onwas elected as an international member of the National Tarantula Model System Academy of Sciences (NAS) in 2018; later, he emi- In 1980 Padr ´onbegan a post- grated to the United States due to his native Venezue- doctoral fellowship at the Medi- la’s ongoing political crisis. Now a professor at the cal Research Council Laboratory University of Massachusetts Medical School, Padr ´on of Molecular Biology (LMB) in answers longstanding questions in his Inaugural Arti- Cambridge, United Kingdom. cle (1) concerning striated muscle contraction that He grew increasingly inter- shed light on its underlying mechanisms in inverte- ested in the work of struc- brates and vertebrates. tural biologist Hugh Huxley, a prominent researcher of mus- Home Laboratory at Age 11 cle physiology who became Padr ´on was born in Caracas to a concert pianist his advisor. Padr ´onproposed mother and pharmacologist and microbiologist father. studying giant barnacle mus- Through his mother he gained a strong work ethic. He cle fibers to learn about their Ra ´ulPadron. ´ Image credit: Marie Craig was also greatly influenced by his father, who main- activation by calcium. Obtain- (photographer). tained a home laboratory. “I still remember my surprise ing the animals proved chal- when he showed me paramecia swimming under a lenging, so Huxley suggested that Padr ´oninstead microscope,” Padr ´onsays. “Soon, I started raising yeast analyze the effect of the ATP analog AMPPNP on chicken soup to see them under magnification.” on muscle structure. Padron ´ examined how this When he was 11 years old, Padr ´onwas permitted compound can arrest the cross-bridge cycle of mus- to have a separate laboratory, where he did chemistry cular contraction (3). The cycle, previously identified and biology experiments and built electronic equip- by Huxley, consists of four basic stages that include ment. He attended San Ignacio High School in Cara- the temporary attachment of the thick filament cas, where mathematician Angel Urmeneta and protein myosin with the thin filament protein actin to biologist Raphael Bredy reinforced his academic in- produce force. terests. In 1966, Bredy suggested that Padr ´onvisit the At the LMB Padr ´onshared an office with fellow Venezuelan Institute for Scientific Research (IVIC). postdoctoral biologist Craig. The duo began a joint During the visit, he met biochemist Karl Gaede, whose project to determine the structure of striated muscle laboratory he joined at age 16. Padr ´onsays, “Under thick filaments. Biophysicist John Wray, who had been Gaede’s advice, I decided to study electrical engi- obtaining X-ray diffraction patterns of invertebrate neering at the Central University of Venezuela, as he muscles, told them that such filaments in tarantula thought this would provide a good background for a muscle were helically ordered and that they should career in biology.” view them using an electron microscope. They fol- Upon earning his undergraduate degree in 1973 lowed his guidance and, in collaboration with col- under electrophysiologist Carlo Caputo, Padr ´onstud- league Anthony Crowther, succeeded in producing ied under molecular biologist Leonardo Mateu at IVIC the first 3D reconstruction of negatively stained taran- for a master’s degree in biology and a doctorate in tula thick filaments (4). The achievement, recounted in a Published under the PNAS license. This is a Profile of a member of the National Academy of Sciences to accompany the member’s Inaugural Article on page 11865 in issue 22 of volume 117. www.pnas.org/cgi/doi/10.1073/pnas.2015960117 PNAS Latest Articles | 1of3 Downloaded by guest on September 30, 2021 book edited by Huxley (5), helped visualize the two muscle; and unicellular organisms (12). They identified heads of a myosin molecule in its native thick filament the IHM, with slight modifications, in all of the studied under relaxed-state conditions. species and in some unicellular organisms. Padron ´ says, “This remarkable conservation highlights the funda- Myosin Interacting-Heads Motif mental importance of the IHM as the structural basis After completing their postdoctoral stints in 1983, underlying relaxation through inhibition of the heads, Craig started his laboratory at the University of Mas- and is likely to underlie a critical energy-saving mecha- sachusetts Medical School and Padr ´onbegan his at nism in cells.” IVIC, where he also served as an associate, senior, and emeritus investigator. Padr ´on,who was awarded the Disease-Associated Mutations and IHM Polar Prize in Biology by the Polar Enterprises Foun- In collaboration with Harvard University professors dation in 1991, additionally served as a visiting pro- Christine and Jonathan Seidman, who study the ge- fessor at the University of Massachusetts, facilitating netic mechanisms of heart disease, Padr ´onand col- what has become a longstanding collaboration with leagues analyzed a model of human cardiac myosin Craig in studying the structure of muscle thick filaments. (13). They discovered that mutations associated with In 1997 the Howard Hughes Medical Institute inherited hypertrophic cardiomyopathy, which is a (HHMI) designated Padr ´on as an international re- condition causing abnormal heart muscle thickness and search scholar, providing an initial 5-year grant that cardiac dysfunction, cluster in the human cardiac IHM at enabled him to found the Department (now Center) of sites of intramolecular interaction. The finding led to Structural Biology at IVIC, equipped with a cryoelec- critical insights concerning the mechanistic basis for the tron microscope, which permits detailed views of hypercontractility, reduced diastolic relaxation, and in- cellular and molecular structures. The HHMI provided creased energy consumption associated with the two additional grants that supported Padr ´on’s labo- disease. ratory until 2011. This and additional research conducted by Padr ´on’s Using a comparable microscope at the University team and other laboratories is being applied to the of Massachusetts, John Woodhead, Craig, Padr ´on, development of therapeutics for cardiomyopathies. and colleagues produced an atomic model of a ta- The Seidmans and biochemist James Spudich, for ex- rantula myosin filament in the relaxed state (6). The 3D ample, are cofounders of the California-based bio- model revealed that, in this state, the two heads of each technology company MyoKardia, which is currently myosin molecule pack together to form an asymmetric conducting late-stage clinical studies of mavacamten, arrangement that inhibits their activity. The authors an investigational therapeutic being developed for the named the asymmetric head organization the myosin treatment of obstructive and nonobstructive forms of “interacting-heads motif” (IHM). hypertrophic cardiomyopathy. The discovery, which was commemorated on a Venezuelan postage stamp in 2007 and helped Padr ´on Challenges Posed by Venezuela Crisis earn the 2008 National Prize of Science of Venezuela, Numerous factors led to the collapse of Venezuela’s enabled the researchers to provide a structural expla- economy, beginning in about 2010. Padr ´on says, nation for muscle relaxation and superrelaxation (high “After my last HHMI grant finished in 2011, keeping inhibition of ATP turnover) (7), as well as activation (8, 9). my [laboratory] running in Venezuela became an ex- The researchers proposed that a cooperative phos- tremely difficult task as the Venezuela crisis contin- phorylation activation (CPA) mechanism regulates my- ued.” Padr ´onand his dedicated team still managed to osin activity. The mechanism holds that the myosin author a pair of seminal “Lessons from a tarantula” heads are phosphorylated sequentially by the enzyme articles, reviewing their research concerning muscle protein kinase C and a myosin light-chain kinase. thick filament and IHM structure, function, and impli- cations for disease (14, 15). Motif Predating Animals As the socioeconomic and political crisis wors- While analyzing the muscle structure of the parasite ened, however, an estimated 5 million individuals left Schistosoma mansoni, Craig, Padr ´on,and their team the country. Padr ´onand his wife, also an IVIC scientist, observed an IHM identical to that identified in taran- became increasingly concerned. (Their four grown tula myosin filaments (10). They were surprised that, children had already left the country.) He says, “My even though the spider and parasite are evolutionarily election as an international member of the NAS in May separate, the IHM and multiple other characteristics of 2018 opened a light at the end of the tunnel.” The these organisms’ muscle structures are similar. Craig’s following month, Craig invited his longstanding col- postdoctoral scholar, Maria Zoghbi (a former student league to join his laboratory at the University
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