The Enzymes

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ISBN: 9780121227258 | 0121227251
Cover: Hardcover
Copyright: 6/19/2006

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Protein methylation has recently emerged as one of the most exciting areas of study on posttranslational modification. A large family of protein methyltransferases has been identified and their structural properties have been characterized. These studies have provided novel insights into how methylation regulates a variety of biological functions including DNA and RNA metabolism, protein synthesis and signal transduction. Methylation also plays important roles in aging. This volume is intended to capture these recent developments concerning protein methyltransferases.

Preface

Part I: Overview of Protein Methyltransferases

1. Protein Methyltransferases: Their Distribution Among the Five Structural Classes of AdoMet-Dependent Methyltransferases

HEIDI L. SCHUBERT, ROBERT M. BLUMENTHAL, AND XIAODONG CHENG

I. Abstract

(1)

II. Introduction

(2)

III. Class I MTases: In the Beginning, an MTase Was an MTase Was an MTase

(3)

IV. Class II MTases: A Lesson in Cobalamin

(1)

V. Class III MTases: Another Lesson in Cobalamin

(3)

VI. Class IV MTases: Knotty New Structure SPOUTs

(2)

VII. Class V MTases: Pseudo Knotty Structures Come in SETs

(2)

VIII. Conformations of AdoMet and AdoHcy

(2)

IX. Diverse Set of Mechanisms for a Conserved Class of MTase

(3)

X. Conclusions

(3)

Acknowledgments

(1)

References

(7)

Part II: Modification of Lysine and Arginine Residues in Signal Transduction, Transcription, Translation, and Other Functions

2. The Family of Protein Arginine Methyltransferases

MARK T. BEDFORD

I. Abstract

(1)

II. Introduction

(1)

III. The Protein Arginine Methyltransferases Family of Enzymes

(2)

IV. Mammalian Protein Arginine Methyltransferases

(6)

V. Yeast Protein Arginine Methyltransferases

(2)

VI. PRMT Substrate Specificity

(1)

VII. Small-Molecule Inhibitors of Protein Arginine Methyltransferases

(1)

References

(7)

3. Diverse Roles of Protein Arginine Methyltransferases

ANNE E. MCBRIDE

I. Abstract

(1)

II. Introduction

(7)

III. Arginine Methylation and Intermolecular Interactions

(2)

IV. Roles of PRMTs in Cellular Processes

(19)

V. Roles of Protein Arginine Methyltransferases in Development and Differentiation

(4)

VI. Roles of Protein Arginine Methyltransferases in Disease

(3)

VII. Conclusions and Future Directions

(2)

Acknowledgments

(1)

References

(16)

4. Structure of Protein Arginine Methyltransferases

XING ZHANG AND XIAODONG CHENG

I. Abstract

105

(1)

II. Protein Arginine Methylation

106

(4)

III. PRMTI

110

(1)

IV. CARM1/PRMT4

111

(1)

V. A Conserved PRMT Core

111

(1)

VI. Structure of the Conserved PRMT Core

112

(1)

VII. PRMT Dimerization is Essential for AdoMet Binding and Enzymatic Activity

112

(2)

VIII. Multiple Substrate Binding Grooves

114

(1)

IX. Asymmetric and Symmetric Dimethylarginines

114

(2)

X. Antagonize Arginine Methylation

116

(1)

Acknowledgments

117

(1)

References

117

(6)

5. Methylation and Demethylation of Histone Arg and Lys Residues in Chromatin Structure and Function

YANMING WANG

I. Abstract

123

(1)

II. Introduction

124

(1)

III. Chromatin Structure and Function

124

(3)

IV. Histone Lys Methylation

127

(9)

V. Histone Lys Demethylase

136

(2)

VI. Histone Arg Methylation and Transcription

138

(3)

VII. Histone Arg Demethylating Enzymes

141

(6)

VIII. Conclusions

147

(1)

References

147

(8)

6. Structure of SET Domain Protein Lysine Methyltransferases

BING XIAO, STEVEN J. GAMBLIN, AND JONATHAN R. WILSON

I. Abstract

155

(1)

II. Introduction

156

(4)

III. SET Domains in Context

160

(1)

IV. Overall Structure

161

(2)

V. Structure of the N- and C-Flanking Domains

163

(2)

VI. The Cofactor Binding Site

165

(1)

VII. Substrate Binding

165

(4)

VIII. Active Site and Methylation

169

(2)

IX. Flexibility of the C-Flanking Domain

171

(2)

References

173

(6)

7. Non-Histone Protein Lysine Methyltransferases: Structure and Catalytic Roles

LYNNETTE M.A. DIRK, RAYMOND C. TRIEVEL, AND ROBERT L. HOUTZ

I. Abstract

179

(1)

II. Introduction

180

(7)

III. Diversity of Polypeptide Substrates

187

(4)

IV. Non-Histone Protein Methyltransferases

191

(23)

V. Conclusions and Future Prospects

214

(2)

Acknowledgments

216

(1)

References

216

(13)

8. Demethylation Pathways for Histone Methyllysine Residues

FEDERICO FORNERIS, CLAUDIA BINDA, MARIA ANTONIETTA VANONI, ANDREA MATTEVI, AND ELENA BATTAGLIOLI

I. Abstract

229

(1)

II. Introduction

230

(1)

III. Histone Demethylation by LSD1 Is a Flavin-Dependent Oxidative Process

231

(4)

IV. LSD1 Is Part of Many Multiprotein Corepressor Complexes

235

(1)

V. Other Proposed Mechanisms for Histone Lysine Demethylation

236

(2)

VI. Conclusions

238

(2)

References

240

(5)

Part III: Biological Regulation by Protein Methyl Ester Formation

9. Structure and Function of Isoprenylcysteine Carboxylmethyltransferase (Icmt): A Key Enzyme in CaaX Processing

JESSICA L. ANDERSON AND CHRISTINE A. HRYCYNA

I. Abstract

245

(1)

II. Introduction

246

(2)

III. Characterization of Icmt Proteins

248

(11)

IV. Cellular Functions of Icmts: Use of Small Molecules to Probe Icmt Function

259

(1)

V. Development of Novel Small-Molecule Icmt Inhibitors

260

(5)

References

265

(8)

10. Genetic Approaches to Understanding the Physiologic Importance of the Carboxyl Methylation of Isoprenylated Proteins

STEPHEN G. YOUNG, STEVEN G. CLARKE, MARTIN O. BERGO, MARK PHILIPS, AND LOREN G. FONG

I. Abstract

273

(1)

II. Introduction

274

(1)

III. STE14 from S. cerevisiae

275

(1)

IV. Biochemical Studies of Icmt Function in Mammals

276

(3)

V. Inactivating Icmt in Mouse Embryonic Stem Cells

279

(2)

VI. Icmt Knockout Mice

281

(2)

VII. Altered Electrophoretic Mobility of Ras Proteins in Icmt-/- Fibroblasts

283

(1)

VIII. Mislocalization of Ras Proteins in Icmt-/- Fibroblasts

284

(2)

IX. Impact of Methylation on the Binding of K-Ras to Microtubules

286

(1)

X. Icmt Is Also Responsible for Methylating the CXC Rab Proteins

287

(1)

XI. Assessing the Impact of Icmt Deficiency on Ras Transformation

287

(6)

XII. An Effect of Icmt Deficiency on Prelamin A Processing

293

(2)

XIII. Phan-nacologic Inhibition of Icmt

295

(2)

Acknowledgments

297

(1)

References

297

(6)

11. Reversible Methylation of Protein Phosphatase 2A

SARI LONGIN AND JOZEF GORIS

I. Abstract

303

(1)

II. PP2A Can Be Reversibly Methylated on Its C-terminal Leucine Residue: The Discovery

304

(1)

III. Methylation of PP2A by a Leucine Carboxyl Methyltransferase (LCMT1)

305

(7)

IV. PP2A-methylesterase (PME-1)

312

(1)

V. The PP2A-PME-PTPA Interplay

313

(1)

VI. Regulation of PP2A Methylation

314

(3)

VII. Conclusions and Perspectives

317

(2)

Acknowledgments

319

(1)

References

319

(6)

12. Reversible Methylation of Glutamate Residues in the Receptor Proteins of Bacterial Sensory Systems

FRANCES M. ANTOMMATTEI AND ROBERT M. WEIS

I. Abstract

325

(1)

II. Introduction

326

(1)

III. The Signaling Pathway

327

(9)

IV. The Methyltranslerase and Its Substrate

336

(31)

V. Conclusions

367

(1)

References

368

(17)

Part IV: Recognition of Damaged Proteins in Aging by Protein Methyltransferases

13. Protein L-Isoaspartyl, D-Aspartyl O-Methyltransferases: Catalysts for Protein Repair

CLARE M. O'CONNOR

I. Abstract

385

(1)

II. Introduction

386

(1)

III. Biochemistry of PIMT-Catalyzed Reactions

387

(9)

IV. Crystallographic Studies of PIMTs

396

(3)

V. Phylogenetic Distribution of PIMT Activities Deduced from Whole Genome Sequences

399

(1)

VI. Biochemistry of Protein Isoaspartyl Methylation In Vivo

400

(8)

VII. Accumulation of Isoaspartyl and Racemized Proteins During Aging

408

(3)

VIII. Physiological Studies of PIMT Function

411

(11)

References

422

(15)

Part V: Modification of Proteins by Methylation of Glutamine and Asparagine Residues

14. Modification of Glutamine Residues in Proteins Involved in Translation

HEIDI L. SCHUBERT

I. Abstract

437

(1)

II. Introduction

438

(1)

III. Ribosomal Protein Methylation

439

(8)

IV. Biological Significance: The Role of Methylated Release Factors

447

(3)

V. The Extended Gln MTase Family

450

(1)

VI. Conclusions

451

(1)

Acknowledgments

451

(1)

References

451

(4)

15. Modification of Phycobiliproteins at Asparagine Residues

ALAN V. KLOTZ

I. Abstract

455

(1)

II. Introduction

455

(1)

III. Occurrence

456

(2)

IV. Biochemistry

458

(1)

V. Potential Functions

459

(1)

VI. Deamidation

459

(1)

VII. Protein Stability

460

(1)

VIII. Specialized Energy Transfer

460

(1)

IX. Conclusions

461

(1)

References

462

(5)

Part VI: Inhibition of Methyltransferases by Metabolites

16. Inhibition of Mammalian Protein Methyltransferases by 5'-Methylthioadenosine (MTA): A Mechanism of Action of Dietary SAMe?

STEVEN G. CLARKE

I. Abstract

467

(1)

II. Introduction

468

(1)

III. Formation and Metabolism of MTA in Mammalian Cells

469

(1)

IV. Usefulness of MTA as a Reagent to Inhibit Protein Methylation in Intact Cells: Mechanism of Action

470

(3)

V. Pharmaceutical AdoMet (SAMe) as an Extracellular Time-Release Form of MTA, Resulting in the Inhibition of Intracellular Methyltransferases?

473

(3)

VI. Effects of MTA on Cellular Functions and Correlation with Effects on Specific Protein Methyltransferases

476

(7)

VII. Biochemical Actions of AdoMet/MTA Not Involving Methyltransferases

483

(2)

VIII. Effects of Dietary AdoMet Not Mediated by Either AdoMet or MTA: Role of Adenosine?

485

(1)

IX. Conclusions

485

(1)

Acknowledgments

486

(1)

References

486

(9)

Author Index

495

(60)

Index

555

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The Enzymes

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