Brenda Schulman, PhD
Brenda A. Schulman, PhD

Brenda A. Schulman, PhD

Member, St. Jude Faculty

  • Co-Leader, Cancer Genetics, Biochemistry & Cell Biology Program
  • Investigator, Howard Hughes Medical Institute

Departments

Education

BA – Johns Hopkins (1989)
PhD – Whitehead Institute/M.I.T. (1996)
Postdoctoral Fellowship
 – MGH Cancer Center/Harvard Medical School (1996-1998)
Postdoctoral Fellowship – Memorial Sloan-Kettering Cancer Center (1998-2001)

Honors & Awards

  • 2014 Elected to the National Academy of Sciences
  • 2012 Elected to the American Academy of Arts and Sciences
  • 2011 Dorothy Crowfoot Hodgkin Award from The Protein Society
  • 2005 Howard Hughes Medical Institute Investigator
  • 2004 Presidential Early Career Award for Scientists and Engineers
  • 2004 Beckman Young Investigator Award
  • 2002 Pew Scholar in Biomedical Sciences Award

Research Interests

  • Post-translational modification by ubiquitin-like proteins
  • Ubiquitin-mediated proteolysis
  • Protein design to understand cell cycle control

The Schulman lab studies the structural basis for post-translational modification by ubiquitin and ubiquitin-like proteins (Ubls). Post-translational covalent attachment of Ubls to protein targets is a primary eukaryotic regulatory mechanism. There are more than a dozen Ubls in higher eukaryotes—such as ubiquitin, NEDD8, ISG15, and SUMO—that covalently modify myriad substrates. The best understood function of a Ubl modification is ubiquitin-mediated proteasomal degradation.  However, different Ubls alter the functions of their targets in different ways, such as by changing the target's subcellular localization, enzymatic activity, or interactions with other proteins or DNA.  Moreover, defects in these pathways have been widely associated with diseases such as cancer, neurodegenerative disorders and viral infections.

Ubls are attached to protein targets by a series of molecular handoffs involving an E1 activating enzyme, an E2 conjugating enzyme (or Ubc), an E3 ligase, and the target. First, at the apex of each Ubl's cascade, a dedicated E1 enzyme selects its Ubl and catalyzes adenylation of the Ubl’s C-terminus.  The E1 then forms a thioester intermediate between the E1's catalytic cysteine and the Ubl's C terminus, and ultimately catalyzes Ubl transfer to an E2's catalytic cysteine to generate a thioester-linked E2~Ubl covalent product.  The E2~Ubl complex typically associates with an E3, which facilitates transfer of the Ubl to the target.

We believe that determining the mechanisms by which enzymes transfer Ubls will be of broad importance, much like studies of protein kinases have influenced our knowledge of signaling pathways and their roles in diseases. Toward this end, the goals of our research are (1) to understand the basic enzymatic mechanisms underlying Ubl attachment to targets, (2) to understand how Ubls are attached selectively, and (3) to understand mechanisms by which Ubl covalent attachment can change enzyme and target function.

Selected Publications

Scott DC, Sviderskiy VO, Monda JK, Lydeard JR, Cho SE, Harper JW, Schulman BA. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157(7):1671-1684, 2014.

Hurley JH, Schulman BA. Atomistic autophagy: the structures of cellular self-digestion. Cell 157(2):300-311, 2014.

Klionsky DJ, Schulman BA. Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat Struct Mol Biol 21(4):336-345, 2014.

Kelsall IR, Duda DM, Olszewski JL, Hofmann K, Knebel A, Langevin F, Wood N, Wightman M, Schulman BA, Alpi AF. TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin-RING ligase complexes. Embo J 32(21):2848-2860, 2013.

Frye JJ, Brown NG, Petzold G, Watson ER, Grace CR, Nourse A, Jarvis MA, Kriwacki RW, Peters JM, Stark H, Schulman BA. Electron microscopy structure of human APC/C(CDH1)-EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nat Struct Mol Biol 20(7):827-835, 2013.

Kamadurai HB, Qiu Y, Deng A, Harrison JS, Macdonald C, Actis M, Rodrigues P, Miller DJ, Souphron J, Lewis SM, Kurinov I, Fujii N, Hammel M, Piper R, Kuhlman B, Schulman BA. Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. Elife 2:e00828, 2013.

Kaiser SE, Mao K, Taherbhoy AM, Yu S, Olszewski JL, Duda DM, Kurinov I, Deng A, Fenn TD, Klionsky DJ, Schulman BA. Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures. Nat Struct Mol Biol 19(12):1242-1249, 2012.

Duda DM, Olszewski JL, Tron AE, Hammel M, Lambert LJ, Waddell MB, Mittag T, DeCaprio JA, Schulman BA. Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Mol Cell 47(3):371-382, 2012.

Kaiser SE, Mao K, Taherbhoy AM, Yu S, Olszewski JL, Duda DM, Kurinov I, Deng A, Fenn TD, Klionsky DJ, Schulman BA. Noncanonical E2 recruitment by the autophagy E1 revealed by Atg7-Atg3 and Atg7-Atg10 structures. Nat Struct Mol Biol November 11, 2012.

Uzunova K, Dye BT, Schutz H, Ladurner R, Petzold G, Toyoda Y, Jarvis MA, Brown NG, Poser I, Novatchkova M, Mechtler K, Hyman AA, Stark H, Schulman BA, Peters JM. APC15 mediates CDC20 autoubiquitylation by APC/C(MCC) and disassembly of the mitotic checkpoint complex. Nat Struct Mol 19(11):1116, 2012.

Lima CD, Schulman BA. Structural biology: a protein engagement RING. Nature 489(7414):43-44, 2012.

Enchev RI, Scott DC, da Fonseca PCA, Schreiber A, Monda JK, Schulman BA, Peter M, Morris EP. Structural basis for a reciprocal regulation between SCF and CSN. Cell Rep 2(3):616-627, 2012.

Duda DM, Olszewski JL, Tron AE, Hammel M, Lambert LJ, Waddell MB, Mittag T, Decaprio JA, Schulman BA. Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Molecular Cell June 26, 2012.

Chaurushiya MS, Lilley CE, Aslanian A, Meisenhelder J, Scott DC, Landry S, Ticau S, Boutell C, Yates JR, Schulman BA, Hunter T, Weitzman MD. Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain. Molecular Cell 46(1):79-90, 2012.

Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, Bahamon BN, Signoretti S, Schulman BA, DeCaprio JA. The glomuvenous malformation protein glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. Molecular Cell 46(1):67-78, 2012.

Taherbhoy AM, Tait SW, Kaiser SE, Williams AH, Deng A, Nourse A, Hammel M, Kurinov I, Rock CO, Green DR, Schulman BA. Atg8 transfer from Atg7 to Atg3: a distinctive E1-E2 architecture and mechanism in the autophagy pathway. Molecular Cell44(3):451-461, 2011

Schulman BA. Twists and turns in ubiquitin-like protein conjugation cascades. Protein Sci 20(12):1941-54, 2011.

Scott DC, Monda JK, Bennett EJ, Harper JW, Schulman BA. N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex. Science September 22, 2011.

Calabrese MF, Scott DC, Duda DM, Grace CR, Kurinov I, Kriwacki RW, Schulman BA. A RING E3-substrate complex poised for ubiquitin-like protein transfer: structural insights into cullin-RING ligases. Nat Struct Mol Biol July 17, 2011.

Duda DM, Scott DC, Calabrese MF, Zimmerman ES, Zheng N, Schulman BA. Structural regulation of cullin-RING ubiquitin ligase complexes. Curr Opin Struct Biol January 31, 2011.

Wang J, Taherbhoy AM, Hunt HW, Seyedin SN, Miller DW, Miller DJ, Huang DT, Schulman BA. Crystal structure of Uba2(ufd)-Ubc9: insights into E1-E2 interactions in Sumo pathways. PLoS One 5(12):e15805, 2010.

Zimmerman ES, Schulman BA, Zheng N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr Opin Struct Biol 20(6):714-721, 2010.

Jubelin G, Taieb F, Duda DM, Hsu Y, Samba-Louaka A, Nobe R, Penary M, Watrin C, Nougayrede JP, Schulman BA, Stebbins CE, Oswald E. Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLoS Pathog 6(9):1128, 2010.

Scott DC, Monda JK, Grace CR, Duda DM, Kriwacki RW, Kurz T, Schulman BA. A Dual E3 mechanism for Rub1 ligation to Cdc53. Molecular Cell 39(5):784-796, 2010.

Schulman BA, Haas AL. Structural Biology: Transformative Encounters. Nature 463: 889-90, 2010.

Reed D, Shen Y, Shelat AA, Arnold A, Ferreira AM, Zhu F, Mills N, Smithson DC, Regni CA, Bashford D, Cicero SA, Schulman BA, Jochemsen AG, Guy RK, Dyer MA. Identification and characterization of the first small-molecule inhibitor of MDMX. Journal of Biological Chemistry 285:10786-96, 2010.

Kamadurai H*, Souphron J*, Scott DC, Duda DM, Miller DJ, Stringer D, Piper RC, Schulman BA. Insights into ubiquitin transfer cascades from a structure of a UbcH5B~Ubiquitin-HECTNEDD4L complex. Molecular Cell 36:1095-102, 2009.

Siergiejuk E, Scott DC, Schulman BA, Hofmann K, Kurz T, Peter M. Cullin neddylation and substrate-adaptors counteract SCF inhibition by the CAND1-like protein Lag2 in Saccharomyces cerevisiae. The EMBO Journal 28:3845-56, 2009.

Zhuang M*, Calabrese MF*, Liu J, Waddell MB, Nourse A, Hammel M, Miller DJ, Walden H, Duda DM, Seyedin SN, Hoggard T, Harper JW, White KP, Schulman BA. Structures of SPOP-Substrate Complexes: Insights into Molecular Architectures of BTB-Cul3 Ubiquitin Ligases. Molecular Cell 36:39-50, 2009.

Wang J, Dye BT, Rajashankar KR, Kurinov I, Schulman BA. Insights into Anaphase Promoting Complex TPR subdomain assembly from a CDC26-APC6 structure. Nature Structural and Molecular Biology 16: 987-989, 2009.

Schulman BA*, Harper JW*. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nature Reviews: Molecular Cell Biology 10: 319-331, 2009. *Equal contributors.

Huang DT*, Ayrault O*, Hunt HW, Taherbhoy A, Duda DM, Scott DC, Borg LA, Neale G, Murray PJ, Roussel, MF1, Schulman BA1. E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification. Molecular Cell 33: 483-495, 2009. *Cover story; Preview, Structure 17:321-322.

Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA. Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation.Cell 134: 995-1006, 2008. *Preview, Cell 135: 209-211.

Souphron J, Waddell MB, Paydar A, Tokgöz-Gromley Z, Roussel MF, Schulman BA. Structural dissection of a gating mechanism preventing misactivation of ubiquitin by NEDD8’s E1. Biochemistry 47: 8961-8969, 2008.

Huang DT, Zhuang M, Ayrault O, Schulman BA. Identification of Conjugation Specificity Determinants Allows Unmasking Vestigial Preference for Ubiquitin within the NEDD8 E2. Nature Structural and Molecular Biology 15:280-287, 2008.

Last update: September 2014