Formation of protein fibrils

Formation of protein fibrils followed by deposition of inorganic material onto the fibril surface

The most abundant protein in animal tissue is collagen which forms the major scaffold of most tissues. It gives definition to and maintains the shape and form of most biological structures. As such, this article will focus on the formation of collagen from its monomeric precursors to its eventual mineralization by surface inorganic salts in hard tissue.

Protein fibril formation is initiated in the nucleus of the eukaryotic cell. The in this case the cell in question is the tenocyte which the functional cell of connective tissue such as ligaments and tendons. The process begins with transcription of the genetic alphabet into specific codons that encode amino acid sequences onto an mRNA strand from a progressively unwinding double helical DNA strand in the 5'→3' direction. Following this transcription, the mRNA floats into the cytosol where it is then appropriately positionedon the rough endoplasmic reticulum between two subunits of an initiator ribosome then subsequently on each of numerous other ribosomes down the mRNA strand. Each ribosomal unit then translates the codon on the mRNA strand into one of 20 amino acids starting with methionine. Proteins synthesis then continues with a step wise elongation to form a polypeptide chain that elongates perpendicularly from the ribosomes. In this chain, the first amino acid, methionine is positioned in a manner that its α-amino acid side occupies the peptidyl site which would then bind to the acceptance (aminoacyl) site of the subsequent amino acid to form a strong peptide bond which competes the primary structure of the eventual protein. Typically, the α-chains of collagen have 1000 amino acids each. In collagen, these amino acids are arranged such that every third amino acid residue if glycine, the smallest amino acid. This has important implications on the ultimate organization of collagen.

In the rough endoplasmic reticulum these α-chains undergo post translational modification which includes but is not limited to glycosylation and hydroxylation of various residues. These reactions are dependent on Vitamin C, manganese and iron as co-factors to catalyse the reactions. In general, each amino acid has different side chains such as but not limited to hydroxyl and sulphate groups, these side chains can bind non-linearly to each other to form other bonds within the or without the polypeptide chain. In the case of collagen, on the amino acid terminal of three consecutive procollagen chains, sulphide residues lead to the formation of disulphide bonds among them to ensure proper alignment of the three chains. These three polypeptide chains are then wound together through bonding with side chains to form procollagen triple helical units. This winding into a triple helix is a product of the arrangement of the amino acid residues as described above. Hydrogen bonding between the α-chains also adds stability to the triple helix. This is the secondary structure of the collagen. These triple helices are then transported to the Golgi apparatus for aggregation and further organization. Here, the COOH- and NH2- pro-peptides are cleaved. This makes the procollagen soluble and it is then transported outside of the cell. In addition, it enables the binding sites of the procollagens to be exposed. This creates electrostatic cross links which further stabilize the procollagen triple helix. These cross links increase the tensile strength of the resultant collagen. Upon secretion from the cell, the procollagen helices are acted upon by procollagen metalloproteinases which convert them into insoluble collagen.This collagen can then bundle up to form the major component of ligaments or tendons or inorganic material may be deposited on its surface to form hard tissue.

Perhaps the most famous mineralized protein fibril inhard tissues such as dentin, bone, cementum and mineralizing cartilage is mineralized collagen. It forms in excess of 80% of the inorganic substance in demineralized hard tissues. In natural bone, the mineralization of collagen is the terminal step of a set of complex steps that are not fully understood even up to today. Deposition of these salts is induced by collagen through self-assembly from soluble procollagen α-chain triple helices and calcium and phosphate precipitates in the aqueous environment of the extracellular environment. In addition, the collagen interacts with trace amounts of cations such as magnesium, anions such as carbonate, hydroxyl, chloride, fluoride, citrate ions among plenty others.  Collagen may arrange itself in parallel and further arrange concentrically as in bone but this leads to  less mineralization than is observed in dentin were collagen fibres form a network with very dense mineral substances. In bone these fibrils are prearranged in a manner that hydroxyapatite crystals nucleate in hole zones of the bone and later are stored between tropocollagen molecules thus generating a lattice of an organic-inorganic nanocomposite. The key players in the deposition of the inorganic substances on the surface of collagen are the matrix vesicles and non-collagenous proteins such as osteonectin and osteocalcin which induce apatite crystal formation by stabilizing the amorphous calcium and phosphate ions to the hierarchical assembly of said apatite within the collagen scaffolding. Their mineralization precedes that of the collagen itself and that of the intervening ground substance. The deposition of these inorganic substances in hard tissues is known to be inhibited by pyrophosphate.

In conclusion, protein fibril formation such as collagen formation is a complex process with numerous intermittent steps. In some instances as in the formation of hard tissue these proteins may be mineralized by deposition of inorganic salts on their surface.

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