Functional diversification within the heme-binding split-barrel family

Grosjean, Nicolas; Zhang, Lifang; Kumaran, Desigan; Xie, Meng; Fahey, Audrey; Santiago, Kassandra; Hu, Fangle; Regulski, Michael; Blaby, Ian K.; Ware, Doreen; Blaby-Haas, Crysten E.

doi:10.1016/j.jbc.2024.107888

Functional diversification within the heme-binding split-barrel family

Journal Article · Fri Oct 11 00:00:00 EDT 2024 · Journal of Biological Chemistry

DOI:https://doi.org/10.1016/j.jbc.2024.107888· OSTI ID:2481979

Grosjean, Nicolas; ; Kumaran, Desigan; Xie, Meng; ; Santiago, Kassandra; Hu, Fangle; Regulski, Michael; Blaby, Ian K.; Ware, Doreen;

Due to neofunctionalization, a single fold can be identified in multiple proteins that have distinct molecular functions. Depending on the time that has passed since gene duplication and the number of mutations, the sequence similarity between functionally divergent proteins can be relatively high, eroding the value of sequence similarity as the sole tool for accurately annotating the function of uncharacterized homologs. Here, we combine bioinformatic approaches with targeted experimentation to reveal a large multifunctional family of putative enzymatic and nonenzymatic proteins involved in heme metabolism. This family (homolog of HugZ (HOZ)) is embedded in the “FMN-binding split barrel” superfamily and contains separate groups of proteins from prokaryotes, plants, and algae, which bind heme and either catalyze its degradation or function as nonenzymatic heme sensors. In prokaryotes these proteins are often involved in iron assimilation, whereas several plant and algal homologs are predicted to degrade heme in the plastid or regulate heme biosynthesis. In the plant Arabidopsis thaliana, which contains two HOZ subfamilies that can degrade heme in vitro (HOZ1 and HOZ2), disruption of AtHOZ1 (AT3G03890) or AtHOZ2A (AT1G51560) causes developmental delays, pointing to important biological roles in the plastid. In the tree Populus trichocarpa, a recent duplication event of a HOZ1 ancestor has resulted in localization of a paralog to the cytosol. Structural characterization of this cytosolic paralog and comparison to published homologous structures suggests conservation of heme-binding sites. This study unifies our understanding of the sequence-structure-function relationships within this multilineage family of heme-binding proteins and presents new molecular players in plant and bacterial heme metabolism.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: U.S. Department of Agriculture; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science (BSS)

Grant/Contract Number:: AC02-05CH11231; SC0012704

OSTI ID:: 2481979

Alternate ID(s):: OSTI ID: 2483246

Report Number(s):: BNL--226405-2024-JAAM

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 11 Vol. 300; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

References (69)

UCSF ChimeraX: Meeting modern challenges in visualization and analysis: UCSF ChimeraX Visualization System Goddard, Thomas D.; Huang, Conrad C.; Meng, Elaine C. Protein Science, Vol. 27, Issue 1 https://doi.org/10.1002/pro.3235	journal	September 2017
Assignment of homology to genome sequences using a library of hidden Markov models that represent all proteins of known structure Gough, Julian; Karplus, Kevin; Hughey, Richard Journal of Molecular Biology, Vol. 313, Issue 4 https://doi.org/10.1006/jmbi.2001.5080	journal	November 2001
Crystal structure of Arabidopsis thaliana glutamyl-tRNAGlu reductase in complex with NADPH and glutamyl-tRNAGlu reductase binding protein Zhao, Aiguo; Han, Feng Photosynthesis Research, Vol. 137, Issue 3 https://doi.org/10.1007/s11120-018-0518-8	journal	May 2018
Identification of a second pyridoxine (pyridoxamine) 5′-phosphate oxidase in Arabidopsis thaliana Sang, Yuying; Goertzen, Leslie R.; Tzou, Ywh-Min Acta Physiologiae Plantarum, Vol. 33, Issue 2 https://doi.org/10.1007/s11738-010-0579-6	journal	August 2010
Novel FMN-binding protein from Desulfovibrio vulgaris (Miyazaki F). Cloning and expression of its gene in Escherichia coli. Kitamura, M.; Kojima, S.; Ogasawara, K. Journal of Biological Chemistry, Vol. 269, Issue 8 https://doi.org/10.1016/S0021-9258(17)37499-9	journal	February 1994
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Precise determination of heme binding affinity in proteins Leung, Galvin C. -H.; Fung, Simon S. -P.; Dovey, Nicholas R. B. Analytical Biochemistry, Vol. 572 https://doi.org/10.1016/j.ab.2019.02.021	journal	May 2019
Crystal structure of Campylobacter jejuni ChuZ: A split-barrel family heme oxygenase with a novel heme-binding mode Zhang, Rui; Zhang, Jinyong; Guo, Gang Biochemical and Biophysical Research Communications, Vol. 415, Issue 1 https://doi.org/10.1016/j.bbrc.2011.10.016	journal	November 2011
Identification of a pyridoxine (pyridoxamine) 5′-phosphate oxidase from Arabidopsis thaliana Sang, Yuying; Barbosa, Jose M.; Wu, Hongzhuan FEBS Letters, Vol. 581, Issue 3 https://doi.org/10.1016/j.febslet.2006.12.028	journal	January 2007
A noncanonical heme oxygenase specific for the degradation of c-type heme Li, Shuxin; Isiorho, Eta A.; Owens, Victoria L. Journal of Biological Chemistry, Vol. 296 https://doi.org/10.1016/j.jbc.2021.100666	journal	January 2021
Sequence–Structure–Function Classification of a Catalytically Diverse Oxidoreductase Superfamily in Mycobacteria Ahmed, F. Hafna; Carr, Paul D.; Lee, Brendon M. Journal of Molecular Biology, Vol. 427, Issue 22 https://doi.org/10.1016/j.jmb.2015.09.021	journal	November 2015
Protein production by auto-induction in high-density shaking cultures Studier, F. William Protein Expression and Purification, Vol. 41, Issue 1, p. 207-234 https://doi.org/10.1016/j.pep.2005.01.016	journal	May 2005
Free heme toxicity and its detoxification systems in human Kumar, Sanjay; Bandyopadhyay, Uday Toxicology Letters, Vol. 157, Issue 3 https://doi.org/10.1016/j.toxlet.2005.03.004	journal	July 2005
The EFI Web Resource for Genomic Enzymology Tools: Leveraging Protein, Genome, and Metagenome Databases to Discover Novel Enzymes and Metabolic Pathways Zallot, Rémi; Oberg, Nils; Gerlt, John A. Biochemistry, Vol. 58, Issue 41 https://doi.org/10.1021/acs.biochem.9b00735	journal	September 2019
A Golden Gate Modular Cloning Toolbox for Plants Engler, Carola; Youles, Mark; Gruetzner, Ramona ACS Synthetic Biology, Vol. 3, Issue 11 https://doi.org/10.1021/sb4001504	journal	February 2014
Crystal structure of human heme oxygenase-1 Poulos, Thomas L.; Schuller, David J.; Wilks, Angela Nature Structural Biology, Vol. 6, Issue 9, p. 860-867 https://doi.org/10.1038/12319	journal	January 1999
A hemoprotein with a zinc-mirror heme site ties heme availability to carbon metabolism in cyanobacteria Grosjean, Nicolas; Yee, Estella F.; Kumaran, Desigan Nature Communications, Vol. 15, Issue 1 https://doi.org/10.1038/s41467-024-47486-z	journal	April 2024
A genome-wide algal mutant library and functional screen identifies genes required for eukaryotic photosynthesis Li, Xiaobo; Patena, Weronika; Fauser, Friedrich Nature Genetics, Vol. 51, Issue 4 https://doi.org/10.1038/s41588-019-0370-6	journal	March 2019
The secreted glycoprotein CREG inhibits cell growth dependent on the mannose-6-phosphate/insulin-like growth factor II receptor Di Bacco, Alessandra; Gill, Grace Oncogene, Vol. 22, Issue 35 https://doi.org/10.1038/sj.onc.1206670	journal	August 2003
A heme degradation enzyme, HutZ, from Vibrio cholerae Uchida, Takeshi; Sekine, Yukari; Matsui, Toshitaka Chemical Communications, Vol. 48, Issue 53 https://doi.org/10.1039/c2cc31147j	journal	January 2012
The Arabidopsis locus AT3G03890 encodes a dimeric β-barrel protein implicated in heme degradation Wang, Jia; Guo, Qi; Li, Xiaoyi Biochemical Journal, Vol. 477, Issue 24 https://doi.org/10.1042/BCJ20200712	journal	December 2020
Characterization of the haem oxygenase protein family in Arabidopsis thaliana reveals a diversity of functions Gisk, Bjoern; Yasui, Yukiko; Kohchi, Takayuki Biochemical Journal, Vol. 425, Issue 2 https://doi.org/10.1042/BJ20090775	journal	December 2009
Floral dip: a simplified method for Agrobacterium-mediated transformation of Arabidopsis thaliana Clough, Steven J.; Bent, Andrew F. The Plant Journal, Vol. 16, Issue 6, p. 735-743 https://doi.org/10.1046/j.1365-313x.1998.00343.x	journal	December 1998
Crystal Structure of HugZ, a Novel Heme Oxygenase from Helicobacter pylori Hu, Yonglin; Jiang, Fan; Guo, Ying Journal of Biological Chemistry, Vol. 286, Issue 2 https://doi.org/10.1074/jbc.M110.172007	journal	October 2010
The Yeast Homolog of Heme Oxygenase-1 Affords Cellular Antioxidant Protection via the Transcriptional Regulation of Known Antioxidant Genes Collinson, Emma J.; Wimmer-Kleikamp, Sabine; Gerega, Sebastien K. Journal of Biological Chemistry, Vol. 286, Issue 3 https://doi.org/10.1074/jbc.M110.187062	journal	November 2010
A Pathway for Repair of NAD(P)H in Plants Colinas, Maite; Shaw, Holly V.; Loubéry, Sylvain Journal of Biological Chemistry, Vol. 289, Issue 21 https://doi.org/10.1074/jbc.M114.556092	journal	May 2014
The Crystal Structures of the Ferric and Ferrous Forms of the Heme Complex of HmuO, a Heme Oxygenase of Corynebacterium diphtheriae Hirotsu, Shoko; Chu, Grace C.; Unno, Masaki Journal of Biological Chemistry, Vol. 279, Issue 12 https://doi.org/10.1074/jbc.M311631200	journal	November 2003
Staphylococcus aureus IsdG and IsdI, Heme-degrading Enzymes with Structural Similarity to Monooxygenases Wu, Ruiying; Skaar, Eric Patrick; Zhang, Rongguang Journal of Biological Chemistry, Vol. 280, Issue 4 https://doi.org/10.1074/jbc.M409526200	journal	October 2004
Heme Oxygenase-1 Protein Localizes to the Nucleus and Activates Transcription Factors Important in Oxidative Stress Lin, Qing; Weis, Sebastian; Yang, Guang Journal of Biological Chemistry, Vol. 282, Issue 28 https://doi.org/10.1074/jbc.M607954200	journal	July 2007
COBALT: constraint-based alignment tool for multiple protein sequences Papadopoulos, J. S.; Agarwala, R. Bioinformatics, Vol. 23, Issue 9 https://doi.org/10.1093/bioinformatics/btm076	journal	March 2007
Protein Subcellular Relocalization of Duplicated Genes in Arabidopsis Liu, Shao-Lun; Pan, An Qi; Adams, Keith L. Genome Biology and Evolution, Vol. 6, Issue 9 https://doi.org/10.1093/gbe/evu191	journal	September 2014
MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability Katoh, K.; Standley, D. M. Molecular Biology and Evolution, Vol. 30, Issue 4 https://doi.org/10.1093/molbev/mst010	journal	January 2013
CRISPR-P: A Web Tool for Synthetic Single-Guide RNA Design of CRISPR-System in Plants Lei, Yang; Lu, Li; Liu, Hai-Yang Molecular Plant, Vol. 7, Issue 9 https://doi.org/10.1093/mp/ssu044	journal	September 2014
The Protein Data Bank Berman, H. M. Nucleic Acids Research, Vol. 28, Issue 1 https://doi.org/10.1093/nar/28.1.235	journal	January 2000
UniProt: the universal protein knowledgebase in 2021 Bateman, Alex; Martin, Maria-Jesus; Orchard, Sandra Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa1100	journal	November 2020
PhycoCosm, a comparative algal genomics resource Grigoriev, Igor V.; Hayes, Richard D.; Calhoun, Sara Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa898	journal	October 2020
The InterPro protein families and domains database: 20 years on Blum, Matthias; Chang, Hsin-Yu; Chuguransky, Sara Nucleic Acids Research, Vol. 49, Issue D1 https://doi.org/10.1093/nar/gkaa977	journal	November 2020
Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation Letunic, Ivica; Bork, Peer Nucleic Acids Research, Vol. 49, Issue W1 https://doi.org/10.1093/nar/gkab301	journal	April 2021
Phytozome: a comparative platform for green plant genomics Goodstein, David M.; Shu, Shengqiang; Howson, Russell Nucleic Acids Research, Vol. 40, Issue D1 https://doi.org/10.1093/nar/gkr944	journal	November 2011
W-IQ-TREE: a fast online phylogenetic tool for maximum likelihood analysis Trifinopoulos, Jana; Nguyen, Lam-Tung; von Haeseler, Arndt Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw256	journal	April 2016
Glutamate 1-semialdehyde aminotransferase is connected to GluTR by GluTR-binding protein and contributes to the rate-limiting step of 5-aminolevulinic acid synthesis Sinha, Neha; Eirich, Jürgen; Finkemeier, Iris The Plant Cell, Vol. 34, Issue 11 https://doi.org/10.1093/plcell/koac237	journal	August 2022
Multiple Heme Oxygenase Family Members Contribute to the Biosynthesis of the Phytochrome Chromophore in Arabidopsis Emborg, Thomas J.; Walker, Joseph M.; Noh, Bosl Plant Physiology, Vol. 140, Issue 3 https://doi.org/10.1104/pp.105.074211	journal	January 2006
Evolution of gene duplication in plants Panchy, Nicholas; Lehti-Shiu, Melissa D.; Shiu, Shin-Han Plant Physiology https://doi.org/10.1104/pp.16.00523	journal	June 2016
An Effective Strategy for Reliably Isolating Heritable and Cas9-Free Arabidopsis Mutants Generated by CRISPR/Cas9-Mediated Genome Editing Gao, Xiuhua; Chen, Jilin; Dai, Xinhua Plant Physiology, Vol. 171, Issue 3 https://doi.org/10.1104/pp.16.00663	journal	May 2016
Flavodiiron Proteins Promote Fast and Transient O ₂ Photoreduction in Chlamydomonas Chaux, Frédéric; Burlacot, Adrien; Mekhalfi, Malika Plant Physiology, Vol. 174, Issue 3 https://doi.org/10.1104/pp.17.00421	journal	May 2017
An Arabidopsis GluTR Binding Protein Mediates Spatial Separation of 5-Aminolevulinic Acid Synthesis in Chloroplasts Czarnecki, Olaf; Hedtke, Boris; Melzer, Michael The Plant Cell, Vol. 23, Issue 12 https://doi.org/10.1105/tpc.111.086421	journal	December 2011
A 5-Enolpyruvylshikimate 3-Phosphate Synthase Functions as a Transcriptional Repressor in Populus Xie, Meng; Muchero, Wellington; Bryan, Anthony C. The Plant Cell, Vol. 30, Issue 7 https://doi.org/10.1105/tpc.18.00168	journal	June 2018
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
A multicolored set of in vivo organelle markers for co-localization studies in Arabidopsis and other plants: Fluorescent organelle markers Nelson, Brook K.; Cai, Xue; Nebenführ, Andreas The Plant Journal, Vol. 51, Issue 6 https://doi.org/10.1111/j.1365-313X.2007.03212.x	journal	August 2007
Increased efficiency of targeted mutagenesis by CRISPR/Cas9 in plants using heat stress LeBlanc, Chantal; Zhang, Fei; Mendez, Josefina The Plant Journal, Vol. 93, Issue 2 https://doi.org/10.1111/tpj.13782	journal	December 2017
Staphylococcus lugdunensis IsdG Liberates Iron from Host Heme Haley, K. P.; Janson, E. M.; Heilbronner, S. Journal of Bacteriology, Vol. 193, Issue 18 https://doi.org/10.1128/JB.00436-11	journal	July 2011
Chlamydomonas reinhardtii LFO1 Is an IsdG Family Heme Oxygenase Lojek, Lisa J.; Farrand, Allison J.; Wisecaver, Jennifer H. mSphere, Vol. 2, Issue 4 https://doi.org/10.1128/mSphere.00176-17	journal	August 2017
Synergistic use of plant-prokaryote comparative genomics for functional annotations Gerdes, Svetlana; El Yacoubi, Basma; Bailly, Marc BMC Genomics, Vol. 12, Issue Suppl 1 https://doi.org/10.1186/1471-2164-12-S1-S2	journal	January 2011
Functional identification of HugZ, a heme oxygenase from Helicobacter pylori Guo, Ying; Guo, Gang; Mao, XuHu BMC Microbiology, Vol. 8, Issue 1 https://doi.org/10.1186/1471-2180-8-226	journal	January 2008
Crystal structure of HutZ, a heme storage protein from Vibrio cholerae: A structural mismatch observed in the region of high sequence conservation Liu, Xiuhua; Gong, Jing; Wei, Tiandi BMC Structural Biology, Vol. 12, Issue 1 https://doi.org/10.1186/1472-6807-12-23	journal	January 2012
Vectors for multi-color bimolecular fluorescence complementation to investigate protein-protein interactions in living plant cells Lee, Lan-Ying; Fang, Mei-Jane; Kuang, Lin-Yun Plant Methods, Vol. 4, Issue 1 https://doi.org/10.1186/1746-4811-4-24	journal	January 2008
Functional diversification of duplicate genes through subcellular adaptation of encoded proteins Marques, Ana C.; Vinckenbosch, Nicolas; Brawand, David Genome Biology, Vol. 9, Issue 3 https://doi.org/10.1186/gb-2008-9-3-r54	journal	March 2008
FastTree 2 – Approximately Maximum-Likelihood Trees for Large Alignments Price, Morgan N.; Dehal, Paramvir S.; Arkin, Adam P. PLoS ONE, Vol. 5, Issue 3 https://doi.org/10.1371/journal.pone.0009490	journal	March 2010
Arabidopsis thaliana PGR7 Encodes a Conserved Chloroplast Protein That Is Necessary for Efficient Photosynthetic Electron Transport Jung, Hou-Sung; Okegawa, Yuki; Shih, Patrick M. PLoS ONE, Vol. 5, Issue 7 https://doi.org/10.1371/journal.pone.0011688	journal	July 2010
Detecting sequence signals in targeting peptides using deep learning Almagro Armenteros, Jose Juan; Salvatore, Marco; Emanuelsson, Olof Life Science Alliance, Vol. 2, Issue 5 https://doi.org/10.26508/lsa.201900429	journal	September 2019
The Structure and Biological Function of CREG Ghobrial, Gaby; Araujo, Luiz; Jinwala, Felecia Frontiers in Cell and Developmental Biology, Vol. 6 https://doi.org/10.3389/fcell.2018.00136	journal	October 2018
HupZ, a Unique Heme-Binding Protein, Enhances Group A Streptococcus Fitness During Mucosal Colonization Lyles, Kristin V.; Thomas, Lamar S.; Ouellette, Corbett Frontiers in Cellular and Infection Microbiology, Vol. 12 https://doi.org/10.3389/fcimb.2022.867963	journal	June 2022
Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes Chiabrando, Deborah; Vinchi, Francesca; Fiorito, Veronica Frontiers in Pharmacology, Vol. 5 https://doi.org/10.3389/fphar.2014.00061	journal	April 2014
Dual Targeting and Retrograde Translocation: Regulators of Plant Nuclear Gene Expression Can Be Sequestered by Plastids Krause, Kirsten; Oetke, Svenja; Krupinska, Karin International Journal of Molecular Sciences, Vol. 13, Issue 9 https://doi.org/10.3390/ijms130911085	journal	September 2012
The age and diversification of the angiosperms re-revisited Bell, Charles D.; Soltis, Douglas E.; Soltis, Pamela S. American Journal of Botany, Vol. 97, Issue 8 https://doi.org/10.3732/ajb.0900346	journal	August 2010
The GluTR-binding protein is the heme-binding factor for feedback control of glutamyl-tRNA reductase Richter, Andreas S.; Banse, Claudia; Grimm, Bernhard eLife, Vol. 8 https://doi.org/10.7554/eLife.46300	journal	June 2019

Similar Records

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
AT1G51560
AT3G03890
AT3G21140
GluTRBP
HOZ
HOZ2A
HOZ2B
chloroplast
iron

Functional diversification within the heme-binding split-barrel family

Citation Formats

References (69)

Similar Records

Related Subjects