Abstract
This chapter (Posttranslational Modifications (PTMs): Alternation of the Three-Dimensional Structure of Proteins) describes posttransitional modification and the manner it affects protein folding. This includes hydroxylation, cysteine formation, gamma-carboxyglutamate, phosphorylation, iodination, glycosylation, glypiation, phosphoglycosylation, lipidation, myristoylation, cysteine palmitoylation, S-prenylation, S-nitrosylation, and ubiquitination.
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Notes
- 1.
Remember, 3,5,3′-triiodothyronine refers to T3. 3,3′,5′-Triiodothyronine refers to a weakly active compound.
- 2.
Signaling pathways (or signal transduction pathways) occur when an environmental molecule such as a hormone attaches to a receptor on the outside of a cell and sets off a cascade of biochemical reactions within the cell.
- 3.
Histidine phosphorylation was thought to involve a minor reaction. But milder methods of isolation of phosphohistidine from proteins suggest that histidine phosphorylation occurs more frequently than originally thought. (Optel CM, Lin MH, Lemeer S (2018) Widespread bacterial protein histidine phosphorylation revealed by mass spectroscopy-based proteomics. Nat Meth, Jan 29, In press, doi: 10.1038/nmeth.4580).
- 4.
EC stands for Enzyme Commission (of the International Union of Biochemistry). The four numbers separated by periods represent a method of identifying the enzyme. The first digit represents one of six main classes, the second digit corresponds to the subclass, the third digit the sub-subclass, and the fourth digit is the serial number. If the EC number is 2.6.1.1; 2 identifies it as a transferase, the 6 indicates that it transfers nitrogenous groups, the 1 that the group transferred is an amino group, and the final 1 is the serial number. The enzyme having that designation is aspartate aminotransferase.
- 5.
The modifications are the addition of other sugars such as galactose and sialic acid.
- 6.
Sequon refers to the sequence of three amino acids on a protein that determines the glycosylation point of an oligosaccharide.
- 7.
The lumen is a sac-like space found in the ER. The lumen is also called the cisternae and is where the nascent protein emerges from the ribosome.
- 8.
The glycan often is Glc3Man9GlcNAc2. This is the glycan usually found in higher eukaryotes.
- 9.
We are using the term “nascent” to describe the protein that is being manufactured off the ribosome.
- 10.
The term saturated means that the myristoyl residue has no double or triple carbon bonds.
- 11.
The Rab family of proteins is a subcategory of the Ras superfamily. Rab family proteins function for vesicle transport, vesicle tethering, and vesicle fusion. All members of the Ras superfamily are prenylated. Nearly 2% of all proteins are prenylated. Rab proteins contain a GTPase region which serves as an on/off switch hydrolyzing guanosine 5′-triphosphate (GTP) to guanosine 5′-diphosphate (GDP). This hydrolysis regulates the functions listed above.
- 12.
Rab geranylgeranyl transferase transfers two geranylgeranyl groups from the diphosphate to two C-terminal cysteine of Rab proteins.
- 13.
More information on nitric oxide can be gained by reading Dods RF. (2013) Complications of diabetes mellitus and their pathophysiology. Ch.8 In: Understanding diabetes: A biochemical perspective. Wiley & Sons, Hoboken, NJ.
- 14.
CREB stands for cAMP response element binding protein. CREB binds to specific sequences on the DNA and decreases or increases transcription of certain genes.
- 15.
T37, T46 is threonine 37, threonine 46.
- 16.
Synaptic plasticity is the strengthening or weakening of synapses in response to other agents such as hormones. We can see how this relates to memory and learning.
- 17.
The region of the ER that faces the cytoplasm. In the rough ER the cytoplasmic surface has the ribosomes embedded in it.
- 18.
The lumen is the interior of the sac (cisternae) located in the rough ER.
Further Reading
Dods RF (1993) Pathophysiology for chemists. ACS, Washington, DC.
Hofsteenge J, Mϋller DR, de Beer T, et al. (1994) New type of linkage a carbohydrate and a protein: C-Glycosylation of a specific tryptophan residue in human RNase Us. Biochemistry:33:13524.
Furmanek A, Hofsteenge J. (2000) Protein C-mannosylation: Facts and questions. Acta Biochim Polonica: 47:781.
Nishikawa T, Adachi M, Isobe M. (2008) C-Glycosylation In: Fraser-Reid B, Tatsuta K, Thiem J, (eds) Glycoscience Springer-Verlag Berlin Heidelberg, Chap. 3.8, p.755. https://doi.org/10.1007/978-3-540-30429-6_17.
Haynes PA, (1998) Phosphoglycosylation: a new structural class of glycosylation? Glycobiology:8:1.
Mehta DP, Ichikawa M, Salimath PV, et al.(1996) A lysosomal cysteine proteinase from Dictyostelium discoideum contains N-acetylglucosamine-1-phosphate bound to serine but not mannose-6-phosphate on N-linked oligosaccharides. J Biol Chem:271:10897.
Greer EL, Shi Y. (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet:13:343. https://doi.org/10.1038/nrg3173.
Verdone L, Agricola E, Caserta M, et al.(2006) Histone acetylation in gene regulation. Brief Funct Genomics:5:209. https://doi.org/10.1093/bfgp/ell028.
Verdin E, Ott M. (2014) 50 Years of protein acetylation: From gene regulation to epigenetics, metabolism and beyond. Nat Rev Mol Cell Biol:16:258. https://doi.org/10.1038/nrm3931.
Jiang H, Zhang X, Chen X, et al. (2018). Protein lipidation: Occurrence, mechanisms, biological functions, and enabling technologies. Chem Rev: in press: https://doi.org/10.1021/acs.chemrev.6b00750.
Diaz-Moreno I, Holingworth D, Frenkiel TA, et al. (2009). Phosphorylation-mediated unfolding of a KH domain regulates KSRP localization via 14-3-3 binding. Nat Struct Mol Biol:16:238. https://doi.org/10.1038/nsmb.1558.
Mitrea DM, Kriwacki RW. (2013). Regulated unfolding of proteins in signaling. FEBS Letters:587:1081. https://doi.org/10.1016/j.febslet.2013.02.024.
Wright PE, Dyson HJ. (2008). Linking folding and binding. Curr Opin Struct Biol:19:31 https://doi.org/10.1016/j.sbi.2008.12.003
Bomblies R, Luitz MP, Zacharias M. (2016. Mechanism of pKID/KIX association studied by molecular dynamics free energy simulations. J Phys Chem B:120:8186. https://doi.org/10.1021/acs.jpcb.6b01792.
Dahal L, Kwan TOC, Shammas SL, et al. (2017) pKID binds to KIX via an unstructured transition state with nonnative interactions. Biophys J:113:2713. https://doi.org/10.1016/j.bpj.2007.10.016.
Bah A, Vernon RM, Siddiqui Z, et al. (2015) Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. Nature:519:106. https://doi.org/10.1038/nature13999.
Zeng J, Jiang F, Wu Y-D. (2017) Mechanism of phosphorylation-induced folding of 4E-BP2 revealed by molecular dynamics simulations. J Chem Theory Comput:13:320. https://doi.org/10.1021/acs.jctc.6b00848.
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Borgia A, Borgia MB, Bugge K, et al. (2018) Extreme disorder in an ultrahigh-affinity protein complex. https://doi.org/10.1038/nature25762.
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Glossary
- Calmodulin
-
is a calcium binding protein.
- Chromatin
-
is a protein wrapped around DNA. When not bonded to DNA, the protein is called euchromatin.
- Collagen
-
consists of repeating motifs; proline-glycine-any amino acid or 4-hydroxyproline-glycine-any amino acid in three helical chains (triple helix) held together by hydrogen bonds and crosslinks between side chains of its amino acids. Collagen is therefore very rope-like with very high tensile strength.
- Kinase
-
is an enzyme that catalyzes the phosphorylation of substances.
- Nucleophilic attack
-
is the reaction of a molecule that is electron rich with a compound that is electron poor. Examples of nucleophilic molecules are :OH−, :NH2−, and :SH−.
- Nucleosomes
-
are complexes of histone and DNA.
- Phosphatase
-
is an enzyme that hydrolyzes a phosphate from a phosphomolecule.
- Signal sequence
-
is a region of amino acids found on a protein that directs it where the protein will be located in the cell.
- Steric hindrance
-
satisfies the rule in physics that states that no two objects can occupy the same space at the same time. Therefore, a molecule can block another molecule from its space by the bulkiness of the groups that compose it. Steric hindrance also borrows another rule from physics that objects with the same electric charge (positive or negative) repel.
- Thioester
-
is a molecule formed by the covalent linkage of an acyl group to an SH.
- Transcriptional activation
-
refers to ribosomal synthesis of proteins.
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Dods, R. (2019). Posttranslational Modifications (PTMs): Alteration of the Three-Dimensional Structure of Proteins. In: Concepts in Bioscience Engineering. Springer, Cham. https://doi.org/10.1007/978-3-030-28303-2_5
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