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Translation and protein synthesis

Last updated: April 21, 2021

Summarytoggle arrow icon

Gene expression is the process by which genetic information flows from DNA to RNA to the protein. The translation of DNA into RNA is termed transcription; protein synthesis from RNA templates is called translation. Details on gene expression and transcription can be found in a separate article.

Translation is carried out by ribosomes, which are large molecular complexes of ribosomal RNA (rRNA) and proteins. Ribosomes bind to RNA templates, also termed messenger RNA (mRNA), and catalyze the formation of a polypeptide based on this template. In the process, a charged transfer RNA (tRNA) recognizes a nucleotide triplet of mRNA that matches a specific amino acid (AA). The new AA is then linked to the next AA of the growing polypeptide on the ribosome. Translation ends once a specific nucleotide sequence of the mRNA is reached (a stop codon). The ribosome subsequently dissociates and the mRNA and newly synthesized protein are released. Before proteins are functional, a proper shape and destination are both necessary. Proteins begin to fold into their three-dimensional structure during translation according to the AA sequence and local chemical forces and reactions. Various specialized proteins (folding catalysts, chaperones) also help the newly formed proteins to fold properly and reach their correct destinations (e.g., cytosol, organelles, extracellular matrix) via protein modifications. The translation rate of proteins is adjusted to the current conditions of the cell and bodily demands, and is affected by the presence or absence of certain nutrients.

The genetic code

Features of the genetic code
Feature Description Exception
Unambiguity (genetic code)
  • Codon is specific to only 1 AA
Commaless, non-overlapping (genetic code)
  • Each codon of the mRNA is translated in the 5' to 3' direction continuously in an open reading frame (ORF)
  • Beginning with the start codon and ending with the stop codon
  • Most viruses
Redundancy, degeneracy (genetic code)
Universality (genetic code)

Stop codons (UAA, UGA, UAG): U Are Away, U Go Away, and U Are Gone.

Start codon: AUG AUthorizes Growth.

  • Description: binding of tRNA to its corresponding AA
  • Relevant enzymes: aminoacyl-tRNA synthetases
  • Reaction mechanism
    1. AA + ATP aminoacyl-AMP + PPi
    2. tRNA + aminoacyl-AMP aminoacyl-tRNA + AMP
  • Mischarged tRNA

Translation occurs in three phases in a functional ribosome: initiation, elongation, and termination; . It requires mRNA, tRNA, and rRNA.

Ribosome binding sites

Eukaryotes have Even-numbered ribosomal subunits (40S + 60S → 80S).
PrOkaryotes have Odd-numbered ribosomal subunits (30S + 50S → 70S).

For binding sites, think of a Growing APE party:
Growing = GTP as the energy source
A site: Arrival with Aminoacyl-tRNA
P site: party of Peptides
E site: party Ends and is Empty;tRNA Exits

Initiation

Elongation

  • Directions of processes
    • mRNA is read in a 5' to 3' direction
    • Elongation occurs in an N-terminus to C-terminus direction: The N-terminus of the growing protein also initially leaves the ribosome.
  • Process

Termination

  • A release factor recognizes the stop codon, halts translation, and hydrolytically cleaves the peptidyl tRNA bonds (requires GTP), leading to release of the protein.

ATP for Activating (charging) tRNA and GTP for tRNA Gripping and Going through the ribosome (translocation) for Growing a polypeptide.

Protein folding

  • Description: The process by which a protein goes from an unfolded native state to form a three-dimensional structure via progressive stabilization of the intermediate states until the most favorable energy level is achieved.
    • Correct protein folding begins during translation and is required for a protein to perform its function within the cell or organism.
  • Intrinsic factors
    • The spatial structure is specified in the AA sequence of the protein (see protein structure for more details).
    • Largely driven by hydrophobic interactions, Van der Waals forces, H+-bonds, salt bridges, disulfide bonds
  • Regulatory proteins: proteins that help other proteins to form their native structure
    • Chaperone proteins
      • Intracellular protein complexes that prevent protein aggregation during synthesis (thus prevent making proteins nonfunctional) and permit refolding of misfolded proteins in a protected environment
      • Assist in transporting (precursor) proteins
      • ATP is consumed in the process.
      • Example: heat shock proteins (e.g., Hsp70, Hsp60, Hsp90)
        • Constitutively expressed proteins that prevent denaturation or misfolding
        • Conditions that lead to increased expression include high temperatures, chemical stress, and hypoxia
    • Folding catalysts: enzymes that accelerate rate-limiting steps during protein folding

Protein misfolding

Overview

Protein glycosylation

N-linked vs. O-linked glycosylation
N-linked glycosylation O-linked glycosylation
Site
% of all glycosylations
  • ∼ 90%
  • ∼ 10%
Attached by
Amino acids involved
Carbohydrate side chains
  • Complex oligosaccharides
  • Less complex oligosaccharides
Sugar residues involved
  • Glucose
  • Mannose
  • Fucose
  • Galactose
  • N-Acetylglucosamine
  • N-Acetylneuraminic acid
  • Galactose
  • N-Acetylgalactosamine
  • N-Acetylglucosamine
  • N-Acetylneuraminic acid
Enzymes/molecules involved
  • Specific glycosyltransferases: oligosaccharyltransferase
  • Dolichol phosphate (in the membrane)
  • Other enzymes, e.g., flippases
  • Specific glycosyltransferases

Sugar attachment to the asparagine residue of proteins (i.e., N-linked glycosylation) begins in the rough ER.

Enzymatic glycosylation should not be confused with nonenzymatic glycation. In glycation, aldoses (e.g., glucose) spontaneously bind to the amino groups of proteins and may influence their function. A classic example is HbA1c, whose function is unaffected by glycation.

Lipid anchors

  • Description
  • Types
    • Acylation: linkage with long chain fatty acids, e.g., palmitic acid
    • Isoprenylation: linkage of a cysteine side chain of the protein with polyisoprene via a thioester bond, such as in:
      • Farnesylation: linkage with a farnesyl residue (three isoprene units, total of 15 C atoms)
      • Geranylgeranylation: linkage with a geranylgeranyl residue (four isoprene units, total of 20 C atoms)
    • GPI anchor: linkage with glycosylphosphatidylinositol (GPI), a glycolipid

Reversible covalent alterations

Enzymatic reversible protein modification alters the protein's spatial structure (conformation), thereby allowing its activity to be regulated. For example, a protein may interact with other proteins and/or become recognizable as a substrate. Reversible protein modification essentially allows the protein to be switched on or off.

Irreversible covalent alterations

  • Citrullination
    • Posttranslational conversion of the amino acid arginine into citrulline, which is relatively more hydrophobic
    • Carried out by peptidylarginine deiminases

Protein trimming

  • Description: the excision of N-terminal or C-terminal propeptides to create a mature protein from an inactive state (e.g., to activate trypsinogen into trypsin)
  • Examples

Protein transportation

A protein's intended final destination depends on its signal sequence (if it has one) at the N-terminus and determines if translation is concluded on free ribosomes or ribosomes on the rough ER.

Overview of protein transportation
Destination Signal sequence Ribosome
Cytosol
  • No
Mitochondria, peroxisomes, or nucleus
  • Yes
Cell membrane, lysosomes, or extracellular (secretory proteins)
  • Yes

Translocation of ribosomes on the rough ER

Overview

Mechanism

  1. Initiation of translation on the free ribosomes in the cytosol
  2. If a signal sequence (specific amino acid sequence of 9–12 amino acids) is synthesized, it is bound to a signal recognition particle (SRP, a cytosolic ribonucleoprotein ).
  3. SRP induces a pause in translation and transports the ribosome with the peptide chain (polypeptide-ribosome complex) across the ER membrane.
  4. SRP facilitates binding of the ribosome with the signal peptide to the SRP receptor on the ER membrane.
  5. SRP and the SRP receptor are both bound to GTP, which is hydrolyzed to GDP; SRP is released and can bind to a new signal sequence.
  6. The ribosome is transferred to a translocon, a protein-lined channel composed of a complex of proteins spanning the ER membrane, with opening of the translocon channel. This translocon is termed the sec61 channel.
  7. Translation resumes and the protein is synthesized in the ER lumen.
  8. The signal sequence is cut off from the growing protein by a signal peptidase.
  9. After termination of translation, the ribosome is released into the cytosol.
  10. The translocon channel closes and the synthesized protein is left in the ER. During translation, the protein is folded into its native conformation.

If the SRP is absent or dysfunctional, there will be an accumulation of proteins in the cytosol of the cell!

Other processes

  • Main component: initiation phase of translation (regulation via initiation factors)
  • Regulation mechanisms
    • Decreased formation of the ternary complex of eIF2, GTP, and initiating tRNA through phosphorylation of the initiation factor eIF2
      • Phosphorylated eIF2 in the GDP-bound form can no longer be converted to its active GTP-bound form. The ternary complex necessary for initiating translation can no longer be formed and the translation rate is reduced.
    • Regulation of the cap recognition process by eIF4