Modifications of the polypeptide chains introduce new functional groups to proteins and extend the repertoire of the standard amino acid residues. More than a hundred modifications have been identified, and modifications occur during (cotranslationally) or after syn thesis of the polypeptide (posttranslationally). Most of the reversible modifications are carried out by enzymes that catalyze the transfer of a chemical group from a donor molecule to the target amino acid. In contrast, proteolytic cleavage of precursor proteins to generate mature products is generally irreversible. The most common protein modifications include acetylation, methylation, myristoylation, prenylation, phosphorylation, sulfation, γ-carboxylation, ubiquitination, sumoylation, and proteolysis. Protein modifications are critical in numerous physiologic processes and central to inherited and acquired diseases. Histone proteins undergo posttranslational modifications (PTMs), such as methylation, acetylation, and others, that modulate the epigenetic code. Here are some features of the most common protein modifications:

• Acetylation: approximately 80% to 90% of human proteins are cotranslationally, irreversibly N-acetylated (acetyl group: COCH3 ). Ribosome-associated Met-aminopeptidases and acetylases cotranslationally cleave off the Nt methionine and acetylate the second residue, respectively. Consequences of Nt-acetylation are manifold, ranging from determining subcellular localization, to regulating protein-protein interactions, to protein folding and other functions. Reversible acetylation can occur posttranslationally on the ε-amino group of lysines, abolishing its positive charge. Besides phosphorylation, lysine acetylation is perhaps the most abundant and important PTM in cell signaling and metabolism.[1]

• Methylation: is the reversible addition of a methyl group (CH3 ) to lysine or arginine residues. This modification increases the hydrophobicity of the protein-altering protein-protein interactions. Protein arginine methylases are explored as therapeutic tar gets in leukemia and other hematologic malignancies.[2,3]

 • Phosphorylation: introduces a charged and hydrophilic phosphate group in the side chains of serine, threonine, or tyrosine with a ratio of occurrence of 1000:100:1 and represents a flexible mechanism for cells to respond to external signals and environmental conditions. Phosphorylation is reversed by the action of protein phosphatases that remove the phosphate group. It has been estimated that the human genome encodes approximately 500 protein kinases and 100 protein phosphatases. The catalytic or biologic activity of many enzymes is transiently regulated by reversible phosphorylation (e.g., switched “on” or “off” by phosphorylation or dephosphorylation, respectively). There are several prominent examples of mutations in tyrosine kinases or their involvement in translocations that result in loss of response and regulation in hematologic diseases, such as mutations in FLT3 in myeloid leukemia, in JAK2 in polycythemia vera, and translocations involving the ABL tyrosine kinase in t(9;22) in chronic myeloid leukemia. All result in constitutive activation providing proliferative and survival advantage to malignant clones.

 • Sulfation: this modification occurs at tyrosine residues and is catalyzed by tyrosyl-protein sulfotransferases (TPSTs), which are membrane-associated enzymes of the trans-Golgi network. An unusual nucleotide, a 3′-phosphoadenosine 5′-phosphosulfate (PAPS), is the universal sulfate donor for TPST-catalyzed reactions. Addition of sulfate occurs almost exclusively on secreted or membrane proteins and is believed to play a role in the modulation of protein-protein interactions. Sulfation is critical in blood coagulation (coagulation factors V and VIII), various immune functions, intracellular trafficking, and ligand recognition by several G protein–coupled receptors.

• γ-Carboxylation: vitamin K is an essential cofactor for the enzyme γ-glutamyl carboxylase (GGCX) that converts glutamate into γ-carboxyglutamate in numerous factors of the clotting cascade, specifically factors II, VII, IX, and X. γ-Glutamyl carboxylation introduces affinity for calcium ions, and its role in coagulation is described in more detail in Box 1.

Box1. Protein γ-Carboxylation: A Rare Posttranslational Modification Crucial for Life

• Ubiquitination: the role of ubiquitination is manifold. It marks proteins for degradation (explained in detail later) and alters their function, their location, and protein-protein interaction. Ubiquitination is achieved by three main steps involving ubiquitin activating and conjugating enzymes, and ubiquitin ligases. Single (monoubiquitination) or multiple (polyubiquitination) ubiquitins can be attached to lysines in target proteins with differing consequences.

 • Sumoylation: small ubiquitin-related modifier (SUMO) proteins are similar to ubiquitin and hence called ubiquitin-like (Ubl). The small peptide SUMO is among the best characterized Ubl, and more than 50 proteins are modified by SUMO addition.

Additional modifications form anchors for membrane association. Among the most important of these modifications are:

• Myristoylation: irreversible attachment of a 14-carbon myristoyl group to the Nt glycine residue of a protein allows association of the target protein with membranes, other proteins, or lipids.

 • Prenylation: involves attachment of the 15-carbon farnesyl group or 20-carbon geranyl group to acceptor proteins that harbor a CAAX consensus sequence (C = cysteine, AA = any aliphatic amino acid except alanine, X = any amino acid) at the C-terminus. Examples of prenylation occur on RAS and RAB protein family members and control their intracellular membrane traffic (see later). Lack of prenylation generates severe phenotypes.

The aforementioned modifications are in general reversible, whereas proteolysis is generally considered an irreversible PTM:

• Proteolysis: results in cleavage of the polypeptide chain at a specific site during its maturation (proinsulin to insulin) or occurs upon secretion of the polypeptide’s inactive form (zymogen). The need for and specific timing of proteolysis prevent unwanted toxic effects of the processed protein in the cell, as is the case for digestive proteases, or direct activation of proteins to specific sites and contexts, as is the case for activation of coagulation factors at sites of damaged blood vessels. Proteolytic processing of pro polypeptides into their mature forms occurs after the Arg-Xxx Lys-Arg motif and is mediated by the protease FURIN. FURIN is ubiquitous and activates clotting factors, growth factors, and other proteases. Other members of the proprotein convertase (PC) family cleave after pairs of dibasic amino acids (e.g., Lys-Arg) and are expressed in specific cell types, such as neuroendocrine cells.

Additional enzymatic modifications (N-glycosylation, O-glycosylation, and attachment of a glycosylphosphatidylinositol [GPI] anchor) are dis cussed later and in Box 1.

In addition to enzymatic reactions, proteins can also undergo nonenzymatic modifications, such as during oxidative stress or in the presence of excess glucose in the blood, as in the case of hemoglobin glycation.

References

--------------

[1] Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein acetylation. Biochim Biophys Acta. 2016;1864(10):1372–1401.

[2] Guccione E, Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol. 2019;20(10):642–657.

[3] Fong JY, Pignata L, Goy PA, et al. Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. Cancer Cell. 2019;36(2):194–209. e199.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الإعلام يشارك في الاجتماع التحضيري لمناقشة الخطة الإعلامية لزيارة عاشوراء

بحضور متوليها الشرعي.. العتبة العباسية المقدسة تواصل إقامة المجالس الحسينية لإحياء شهر المحرم

قسم الشؤون الفكرية يطلق برنامجه التبليغي في أكثر من 20 دولة إفريقية

شعبتا الخطابة النسوية والتوجيه الديني تواصلان إقامة المجالس الحسينية في مرقد أبي الفضل العباس (عليه السلام)

المزيد

الآخبار الصحية

دراسة تكشف علاقة خطيرة بين عمر الأم وصحة مولودها

دراسة تحذر.. اضطراب نوم بسيط قد يسبب الموت المبكر ؟

الاستحمام بالماء الساخن.. راحة مؤقتة وأضرار دائمة للبشرة

ماذا يحدث للجسم عند تخطي وجبة الإفطار؟

المزيد

الآخبار التكنلوجية

كيف تساعد الصيانة الوقائية في الحفاظ على كفاءة التكييف في سيارتك ؟

في ظاهرة غريبة حيرت العلماء.. كوكبنا قد يسجل أقصر يوم في التاريخ هذا الصيف!

السد الصيني العملاق يعيق دوران الأرض ويغيّر شكلها ؟

السعودية تطلق 10 تجارب علمية إلى محطة الفضاء الدولية

المزيد

مواضيع ذات صلة

How AraC Protein Loops and Unloops

DNA Looping and Repression of araBAD

Binding Sites of the ara Regulatory Proteins

Endoplasmic Reticulum-Associated Degradation and the Unfolded Protein Response

Protein Folding and Modifications in the Endoplasmic Reticulum

Regulating AraC Synthesis

Repression by AraC

Detection and Isolation of AraC Protein

Genetics of the Arabinose System

The Eukaryotic Genome

Nucleic Acids and Their Organization in Eukaryotic, Prokaryotic, and Viral Genomes

The Sugar Arabinose and Arabinose Metabolism