Meta-Biol

• Pathways

While circularization of mRNA during translation initiation is thought to contribute to an increase in the efficiency of translation, it also appears to provide a mechanism for translational silencing. This might be achieved by bringing inhibitory 3' UTR-binding proteins into a position in which they interfere either with the function of the translation initiation complex or with the assembly of the ribosome (Mazumder et al 2001). Translational silencing of Ceruloplasmin (Cp) occurs 16 hrs after its induction by INF-gamma (Mazumder et al., 1997). Although the mechanism by which silencing occurs has not yet been determined, this process is mediated by the L13a subunit of the 60s ribosome and thought to require circularization of the Cp mRNA (Sampath et al., 2003; Mazumder et al., 2001; Mazumder et al., 2003). Between 14 and 16 hrs after INF gamma induction, the L13a subunit of the 60s ribosome is phosphorylated and released from the 60s subunit. Phosphorylated L13a then associates with the GAIT element in the 3' UTR of the Cp mRNA inhibiting its translation.

Protein synthesis is accomplished through the process of translation of an mRNA sequence into a polypeptide chain. This process can be divided into three distinct stages: initiation, elongation and termination. During the initiation phase, the two subunits of the ribosome are brought together to the translation start site on the mRNA where the polypeptide chain is to begin. Extension of the polypeptide chain occurs when a specific aminoacyl-tRNA, as determined by the template mRNA, binds an elongating ribosome. The protein chain is released from the ribosome when any one of three stop codons in the relevant reading frame on the mRNA is reached. Individual reactions at each one of these stages are catalyzed by a number of initiation, elongation and release factors, respectively.
Proteins destined for the endoplasmic reticulum (ER) contain a short sequence of hydrophobic amino acid residues (approximately 20 residues) at their N-termini. Upon protrusion of the signal sequence from the translating ribosome, the signal sequence is bound by the cytosolic signal recognition particle (SRP), translation is temporarily halted, and the SRP:nascent peptide:ribosome complex then docks with a SRP receptor complex on the ER membrane. There the nascent peptide:ribosome complex is transferred from the SRP complex to a translocon complex embedded in the ER membrane and reoriented so that the nascent polypeptide protrudes through a pore in the translocon into the ER lumen. Translation now resumes, the signal peptide is cleaved from the polypeptide by signal peptidase as the signal peptide emerges into the ER, and elongation proceeds with the growing polypeptide oriented into the ER lumen.
The 13 proteins encoded by the mitochondrial genome are translated within the mitochondrion by mitochondrial ribosomes (mitoribosomes) at the matrix face of the inner mitochondrial membrane. Mitochondrial translation reflects both the bacterial origin of the organelle and subsequent divergent evolution during symbiosis. Mitoribosomes have shorter rRNAs, mitochondria-specific proteins, and rearranged protein positions. Mitochondrial mRNAs have either no untranslated leaders or very short untranslated leaders of 1-3 nucleotides. Translation begins with N-formylmethionine, as in bacteria, and continues with cycles of aminoacyl-tRNA:TUFM:GTP binding, GTP hydrolysis and dissociation of TUFM:GDP. All 13 proteins encoded by the mitochondrial genome are hydrophobic inner membrane proteins which are inserted cotranslationally into the membrane by an interaction with OXA1L. Translation is terminated when MTRF1L:GTP recognizes a UAA or UAG codon at the A-site of the mitoribosome. The translated polypeptide is released and MRRF and GFM2:GTP act to dissociate the 55S ribosome into 28S and 39S subunits.

Metabolism of proteins, as annotated here, covers the full life cycle of a protein from its synthesis to its posttranslational modification and degradation, at various levels of specificity. Protein synthesis is accomplished through the process of Translation of an mRNA sequence into a polypeptide chain. Protein folding is achieved through the function of molecular chaperones which recognize and associate with proteins in their non-native state and facilitate their folding by stabilizing the conformation of productive folding intermediates (Young et al. 2004). Following translation, many newly formed proteins undergo Post-translational protein modification, essentially irreversible covalent modifications critical for their mature locations and functions (Knorre et al. 2009), including gamma carboxylation, synthesis of GPI-anchored proteins, asparagine N-linked glycosylation, O-glycosylation, SUMOylation, ubiquitination, deubiquitination, RAB geranylgeranylation, methylation, carboxyterminal post-translational modifications, neddylation, and phosphorylation. Peptide hormones are synthesized as parts of larger precursor proteins whose cleavage in the secretory system (endoplasmic reticulum, Golgi apparatus, secretory granules) is annotated in Peptide hormone metabolism. After secretion, peptide hormones are modified and degraded by extracellular proteases (Chertow, 1981 PMID:6117463). Protein repair enables the reversal of damage to some amino acid side chains caused by reactive oxygen species. Pulmonary surfactants are lipids and proteins that are secreted by the alveolar cells of the lung that decrease surface tension at the air/liquid interface within the alveoli to maintain the stability of pulmonary tissue (Agassandian and Mallampalli 2013). Nuclear regulation, transport, metabolism, reutilization, and degradation of surfactant are described in the Surfactant metabolism pathway. Amyloid fiber formation, the accumulation of mostly extracellular deposits of fibrillar proteins, is associated with tissue damage observed in numerous diseases including late phase heart failure (cardiomyopathy) and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.