CHRISTINE ORENGO, PhD, is Professor of Bioinformatics at University College London. Dr. Orengo's research focuses on protein structure comparison, classification, and analysis. Her group develops the CATH domain family classification and algorithms for predicting protein functions and functional networks.ALEX BATEMAN, PhD, is Senior Investigator at Wellcome Trust Sanger Institute, where he leads the Pfam database project. Dr. Bateman also participates in the European InterPro project, which seeks to merge the annotations from Pfam, PRINTS, Prosite, and other domain databases.

• Introduction viiContributors xiiiSECTION I. CONCEPTS UNDERLYING PROTEIN FAMILY CLASSIFICATION 11 Automated Sequence-Based Approaches for Identifying Domain Families 3Liisa Holm and Andreas Heger2 Sequence Classification of Protein Families: Pfam and other Resources 25Alex Bateman3 Classifying Proteins into Domain Structure Families 37Alison Cuff, Alexey Murzin, and Christine Orengo4 Structural Annotations of Genomes with Superfamily and Gene3D 69Julian Gough, Corin Yeats, and Christine Orengo5 Phylogenomic Databases and Orthology Prediction 99Kimmen Sj¨olanderSECTION II. IN-DEPTH REVIEWS OF PROTEIN FAMILIES 1256 The Nucleophilic Attack Six-Bladed β-Propeller (N6P) Superfamily 127Michael A. Hicks, Alan E. Barber II, and Patricia C. Babbitt7 Functional Diversity of the HUP Domain Superfamily 159Benoit H. Dessailly and Christine Orengo8 The NAD Binding Domain and the Short-Chain Dehydrogenase/Reductase (SDR) Superfamily 191Nicholas Furnham, Gemma L. Holliday, and Janet M. Thornton9 The Globin Family 207Arthur M. Lesk and Juliette T.J. LecomteSECTION III. REVIEW OF PROTEIN FAMILIES IN IMPORTANT BIOLOGICAL SYSTEMS 23710 Functional Adaptation and Plasticity in Cytoskeletal Protein Domains: Lessons from the Erythrocyte Model 239Anthony J. Baines11 Unusual Species Distribution and Horizontal Transfer of Peptidases 285Neil D. Rawlings12 Deducing Transport Protein Evolution Based on Sequence, Structure, and Function 315Steven T. Wakabayashi, Maksim A. Shlykov, Ujjwal Kumar, Vamsee S. Reddy, Ankur Malhotra, Erik L. Clarke, Jonathan S. Chen, Rostislav Castillo, Russell De La Mare, Eric I. Sun, and Milton H. Saier13 Crispr-CAS Systems and CAS Protein Families 341Kira S. Makarova, Daniel H. Haft, and Eugene V. Koonin14 Families of Sequence-Specific DNA-Binding Domains in Transcription Factors across the Tree of Life 383Varodom Charoensawan and Sarah Teichmann15 Evolution of Eukaryotic Chromatin Proteins and Transcription Factors 421L. Aravind, Vivek Anantharaman, Saraswathi Abhiman, and Lakshminarayan M. IyerIndex 503

CHRISTINE ORENGO, PhD, is Professor of Bioinformatics at University College London. Dr. Orengo's research focuses on protein structure comparison, classification, and analysis. Her group develops the CATH domain family classification and algorithms for predicting protein functions and functional networks.ALEX BATEMAN, PhD, is Senior Investigator at Wellcome Trust Sanger Institute, where he leads the Pfam database project. Dr. Bateman also participates in the European InterPro project, which seeks to merge the annotations from Pfam, PRINTS, Prosite, and other domain databases.

• Introduction viiContributors xiiiSECTION I. CONCEPTS UNDERLYING PROTEIN FAMILY CLASSIFICATION 11 Automated Sequence-Based Approaches for Identifying Domain Families 3Liisa Holm and Andreas Heger2 Sequence Classification of Protein Families: Pfam and other Resources 25Alex Bateman3 Classifying Proteins into Domain Structure Families 37Alison Cuff, Alexey Murzin, and Christine Orengo4 Structural Annotations of Genomes with Superfamily and Gene3D 69Julian Gough, Corin Yeats, and Christine Orengo5 Phylogenomic Databases and Orthology Prediction 99Kimmen Sj¨olanderSECTION II. IN-DEPTH REVIEWS OF PROTEIN FAMILIES 1256 The Nucleophilic Attack Six-Bladed β-Propeller (N6P) Superfamily 127Michael A. Hicks, Alan E. Barber II, and Patricia C. Babbitt7 Functional Diversity of the HUP Domain Superfamily 159Benoit H. Dessailly and Christine Orengo8 The NAD Binding Domain and the Short-Chain Dehydrogenase/Reductase (SDR) Superfamily 191Nicholas Furnham, Gemma L. Holliday, and Janet M. Thornton9 The Globin Family 207Arthur M. Lesk and Juliette T.J. LecomteSECTION III. REVIEW OF PROTEIN FAMILIES IN IMPORTANT BIOLOGICAL SYSTEMS 23710 Functional Adaptation and Plasticity in Cytoskeletal Protein Domains: Lessons from the Erythrocyte Model 239Anthony J. Baines11 Unusual Species Distribution and Horizontal Transfer of Peptidases 285Neil D. Rawlings12 Deducing Transport Protein Evolution Based on Sequence, Structure, and Function 315Steven T. Wakabayashi, Maksim A. Shlykov, Ujjwal Kumar, Vamsee S. Reddy, Ankur Malhotra, Erik L. Clarke, Jonathan S. Chen, Rostislav Castillo, Russell De La Mare, Eric I. Sun, and Milton H. Saier13 Crispr-CAS Systems and CAS Protein Families 341Kira S. Makarova, Daniel H. Haft, and Eugene V. Koonin14 Families of Sequence-Specific DNA-Binding Domains in Transcription Factors across the Tree of Life 383Varodom Charoensawan and Sarah Teichmann15 Evolution of Eukaryotic Chromatin Proteins and Transcription Factors 421L. Aravind, Vivek Anantharaman, Saraswathi Abhiman, and Lakshminarayan M. IyerIndex 503

CHRISTINE ORENGO, PhD, is Professor of Bioinformatics at University College London. Dr. Orengo's research focuses on protein structure comparison, classification, and analysis. Her group develops the CATH domain family classification and algorithms for predicting protein functions and functional networks.ALEX BATEMAN, PhD, is Senior Investigator at Wellcome Trust Sanger Institute, where he leads the Pfam database project. Dr. Bateman also participates in the European InterPro project, which seeks to merge the annotations from Pfam, PRINTS, Prosite, and other domain databases.

• Introduction viiContributors xiiiSECTION I. CONCEPTS UNDERLYING PROTEIN FAMILY CLASSIFICATION 11 Automated Sequence-Based Approaches for Identifying Domain Families 3Liisa Holm and Andreas Heger2 Sequence Classification of Protein Families: Pfam and other Resources 25Alex Bateman3 Classifying Proteins into Domain Structure Families 37Alison Cuff, Alexey Murzin, and Christine Orengo4 Structural Annotations of Genomes with Superfamily and Gene3D 69Julian Gough, Corin Yeats, and Christine Orengo5 Phylogenomic Databases and Orthology Prediction 99Kimmen Sj¨olanderSECTION II. IN-DEPTH REVIEWS OF PROTEIN FAMILIES 1256 The Nucleophilic Attack Six-Bladed β-Propeller (N6P) Superfamily 127Michael A. Hicks, Alan E. Barber II, and Patricia C. Babbitt7 Functional Diversity of the HUP Domain Superfamily 159Benoit H. Dessailly and Christine Orengo8 The NAD Binding Domain and the Short-Chain Dehydrogenase/Reductase (SDR) Superfamily 191Nicholas Furnham, Gemma L. Holliday, and Janet M. Thornton9 The Globin Family 207Arthur M. Lesk and Juliette T.J. LecomteSECTION III. REVIEW OF PROTEIN FAMILIES IN IMPORTANT BIOLOGICAL SYSTEMS 23710 Functional Adaptation and Plasticity in Cytoskeletal Protein Domains: Lessons from the Erythrocyte Model 239Anthony J. Baines11 Unusual Species Distribution and Horizontal Transfer of Peptidases 285Neil D. Rawlings12 Deducing Transport Protein Evolution Based on Sequence, Structure, and Function 315Steven T. Wakabayashi, Maksim A. Shlykov, Ujjwal Kumar, Vamsee S. Reddy, Ankur Malhotra, Erik L. Clarke, Jonathan S. Chen, Rostislav Castillo, Russell De La Mare, Eric I. Sun, and Milton H. Saier13 Crispr-CAS Systems and CAS Protein Families 341Kira S. Makarova, Daniel H. Haft, and Eugene V. Koonin14 Families of Sequence-Specific DNA-Binding Domains in Transcription Factors across the Tree of Life 383Varodom Charoensawan and Sarah Teichmann15 Evolution of Eukaryotic Chromatin Proteins and Transcription Factors 421L. Aravind, Vivek Anantharaman, Saraswathi Abhiman, and Lakshminarayan M. IyerIndex 503