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Understanding and Predicting Transcription Factor Specificities Richard S. Mann C2B2/MAGNet Center Third Annual Retreat April 11, 2008 Signal Transduction Transcriptional control by multiprotein complexes p50 p65 Signal integration Vast combinatorial ensembles with a min number of factors Evolvability from Wolberger C., 1999 Drosophila Hox genes Abd-B lab abd-A Dfd Ubx Scr Antp Dave Kosman, UCSD Hox factors: molecular architects of morphological diversity D. melanogaster zen lab bcd pb ftz Dfd Scr head Antp thorax Ubx abd-A abd-B abdomen A P Mus musculus Hoxa1 Hoxa2 Hoxa3 Hoxa4 Hoxa5 Hoxa6 Hoxa7 Hoxb1 Hoxb2 Hoxb3 Hoxb4 Hoxb5 Hoxb6 Hoxb7 Hoxc4 Hoxc5 Hoxc6 Hoxd1 Hoxd3 Hoxd4 Hoxa9 Hoxa10 Hoxa11 Hoxa13 Hoxb8 Hoxb9 Hoxa13 Hoxc8 Hoxc9 Hoxc10 Hoxc11 Hoxc12 Hoxc13 Hoxd8 Hoxd9 Hoxd10 Hoxd11 Hoxd12 Hoxd13 Adapted from Perason J.C. et al., 2005 Problem of Hox specificity: Paradox 1 Homeodomain YPWM linker N-term arm 1 Lab Pb Dfd Scr Antp Ubx Abd-A Abd-B helix 1 10 20 helix 2 30 helix 3 40 50 60 TYKWMQ(109)NNSGRTNFTNKQLTELEKEFHFNRYLTRARRIEIANTLQLNETQVKIWFQNRRMKQKKRV EYPWMK(28) PRRLRTAYTNTQLLELEKEFHFNKYLCRPRRIEIAASLDLTERQVKVWFQNRRMKHKRQT IYPWMK(17) PKRQRTAYTRHQILELEKEFHYNRYLTRRRRIEIAHTLVLSERQIKIWFQNRRMKWKKDN IYPWMK(14) TKRQRTSYTRYQTLELEKEFHFNRYLTRRRRIEIAHALCLTERQIKIWFQNRRMKWKKEH LYPWMR (8) RKRGRQTYTRYQTLELEKEFHFNRYLTRRRRIEIAHALCLTERQIKIWFQNRRMKWKKEN FYPWMA (7) RRRGRQTYTRYQTLELEKEFHTNHYLTRRRRIEMAHALCLTERQIKIWFQNRRMKLKKEI RYPWMT(24) RRRGRQTYTRFQTLELEKEFHFNHYLTRRRRIEIAHALCLTERQIKIWFQNRRMKLKKEL LHEWTG (3) VRKKRKPYSKFQTLELEKEFLFNAYVSKQKRWELARNLQLTERQVKIWFQNRRMKNKKNS identical residues make DNA contacts Paradox 2: most Hox proteins bind to very similar ‘AT’ rich binding sites Paradox 3: residues important for specificity are usually disordered Ubx YPWM Exd Passner, Aggarwal Salivary Gland D. Andrew; BioEssays 23:901-911 A P Fkh Distinct properties of Hox-Exd binding sites fkh250 Exd Scr AGATTAATCG paralog specific fkh250con Exd Hox AGATTTATGG shared Ryoo et al., 1999 fkh250con fkh250 His–12 Arg3 Passner, Jain, Aggarwal fkh250 has two minor groove width minima that dictate electrostatic potential Rohs, Sosinsky, Honig Recognition of DNA SHAPE ‘Specific’ Hox-DNA contacts Base-specific hydrogen bonds ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 helix 3 ‘Specific’ Hox-DNA contacts ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 helix 3 ‘Specific’ Hox-DNA contacts ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 What are the global DNA binding specificities? helix 3 What are the range of DNA recognition modes? How general is this mechanism? ‘Specific’ Hox-DNA contacts ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 What are the global DNA binding specificities? helix 3 What are the range of DNA recognition modes? How general is this mechanism? His–12 and Arg3 are among Scr’s ‘signature’ residues YPWM His–12 LINKER HOMEODOMAIN Arg3 Lab Pb Dfd Scr Antp Lab XD1 mA1 hB1 xA1 CB1 MB1 PB HB2 HB3 HD3 MB3 DFD CD4 MD4 HD4 MA4 HA4 CA4 CB4 MB4 HC4 MC4 XB4 Scr MA5 HA5 MB5 HB5 XB5 HC5 ANT CB8 MB8 XB8 CD8 MD8 MC8 UBX XB7 HB7 MB7 XA7 CA7 MA7 ABA MC6 HC6 XC6 MB6 HB6 Ubx AbdA Hox6 SSIPTYKWMQLKRNVP SYVSTFDWMKVKRNPP SPAQTFDWMKVKRNPP PTARTFDWMKVKRNPP GPTQTFDWMKVKRNPP SRARTFDWMKVKRNPP LTPRTFDWMKVKRNPP DSVPEYPWMKEKKTSR PPAPEFPWMKEKKSAK LTKQIFPWMKESRQTS ISKQIFPWMKESRQNS LTKQIFPWMKESRQTS GERIIYPWMKKIHVAG QPAVVYPWMKKVHVNS QPAVVYPWMKKVHVNS QPAVVYPWMKKVHVNS KEPVVYPWMKKIHVSA KEPVVYPWMKKIHVSA KEPVVYPWMKKIHVST KEPVVYPWMKKVHVST KEPVVYPWMRKVHVST KQPIVYPWMKKIHVST KQPIVYPWMKKIHVST QDPVVYPWMKKAHISK NPPQIYPWMKRVHLGT AQPQIYPWMRKLHISH AQPQIYPWMRKLHISH QTPQIFPWMRKLHISH QSPQIFPWMRKLHINH QSPQIFPWMRKLHINH QPPQIYPWMTKLHMSH MPSPLYPWMRSQPGKC SPTQLFPWMRPQAAAG SPTQLFPWMRPQAAAG SPTQLFPWMRPQAAGR SPAQMFPWMRPQAAPG SPSQMFPWMRPQAAPG SPSLMFPWMRPHAPGR SNHTFYPWMAIAGECP ANLRIYPWMRSAGADR SNFRIYPWMRSSGTDR SNFRIYPWMRSSGPDR SHFRIYPWMRSSGPDR ANFRIYPWMRSSGPDR ASFRIYPWMRSSGPDR ADLPRYPWMTLTDWMG ASIQIYPWMQRMNSHS ASIQIYPWMQRMNSHS GSIQIYPWMQRMNSHS CSTPVYPWMQRMNSCN CSTPVYPWMQRMNSCN Paralog-specific ‘signature’ residues surrounding the YPWM motif Fkh250 Fkh250con Scr Kd ~10nM Kd ~12nM Kd ~20nM Kd ~40nM Kd >300nM Kd ~30nM Dfd Ubx Dfd is a repressor of fkh250 Fkh250 Dfd Two steps in Hox specificity Hox Hox binding site DNA binding cofactors Hox binding site Regulation Act Rep ‘Specific’ Hox-DNA contacts ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 What are the global DNA binding specificities? helix 3 What are the range of DNA recognition modes? How general is this mechanism? Cognate Sequence Identifier (CSI) Aseem Ansari Correlation between Exd and Dfd binding Karl Haucshild and Aseem Ansari Exd+Scr Exd+Ubx Sequences that prefer Scr-Exd Sequences that prefer Ubx-Exd Exd Dfd Karl Haucshild and Aseem Ansari ‘Specific’ Hox-DNA contacts ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 What are the global DNA binding specificities? helix 3 What are the range of DNA recognition modes? How general is this mechanism? Hox cofactor DNA Scr Exd fkh250 Dfd Exd fkh250 Lab Exd Lab48/95 Ubx Exd DllR AbdA Exd DllR AbdA En DllR ? Xiangshu Jin DNA shape varies among Hox binding sites Fkh250con Fkh250 All Hox? Scr, Dfd DllR Lab48/95 Ubx, AbdA Lab Lab Ebner Lab Remo Rohs, Barry Honig ‘Specific’ Hox-DNA contacts ‘General’ Hox-DNA contacts homeodomain YPWM linker N-term arm helix 1 helix 2 What are the global DNA binding specificities? helix 3 What are the range of DNA recognition modes? How general is this mechanism? Rohit Joshi Jonathan Passner Rinku Jain Aneel Aggarwal Remo Rohs Alona Sosinsky Barry Honig Xiangshu Jin Karl Hauschild Aseem Ansari Andrea Califano
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