NBME 21 Answers ↦
A 1-year-old girl is admitted to the hospital ...
Disruption of the secondary structure of collagen molecules🔍
I figured, glycine-X-Y is technically considered a “primary amino acid structure of a protein” since the definition of a Primary structure of a protein is “a linear chain of amino acids.” If you mess with the Primary structure, as in the question stem, you cannot form the Secondary structure of the protein, which is determined by the hydrogen-bonding which occurs between the peptide backbone, independent of the R groups. I hope this made sense.
From wikipedia: “Secondary structure is formally defined by the pattern of hydrogen bonds between the amino hydrogen and carboxyl oxygen atoms in the peptide backbone.” (emphasis mine)
From Molecular Biology of the Cell:
Biologists distinguish four levels of organization in the structure of a protein. The amino acid sequence is known as the primary structure of the protein. Stretches of polypeptide chain that form α helices and β sheets constitute the protein’s secondary structure. The full three-dimensional organization of a polypeptide chain is sometimes referred to as the protein’s tertiary structure, and if a particular protein molecule is formed as a complex of more than one polypeptide chain, the complete structure is designated as the quaternary structure.
Due to glycine's small size, it creates "kinks" in the amino acid sequence. These kinks are needed to correctly form the secondary structure.
Other answers:
- "weakened interaction between collagen and proteoglycan" - collagen + proteoglycan = cartillage. The question stem mentions many defects in bONE (type I collagen) but no mention of defects in carTWOllage (type II collagen)
ok guys and i quote from https://www.orthobullets.com/pediatrics/4102/osteogenesis-imperfecta
"90% have an identifiable genetic mutation
COL 1A1 and COL 1A2
causes abnormal collagen cross-linking via a glycine substitution in the procollagen molecule "
which means that OI has a glycine substitution and therfore its unable to form a secondary sturucture.
I might be overthinking it but, H bond formation of aa's makes the secondary structure of the protein (collagen in this case). The Gly to Ala substitution does result in less H bond formation, but of individual aa's not between collagen molecules (that might be more for quaternary structure)
Here’s one way to process-of-eliminate “decreased hydrogen-bond formation”: I’m not a big fan of this line of reasoning, but technically alanine as a side group has more hydrogens* for potential hydrogen bonding than glycine:
alanine: —CH3
glycine: —H
So, “technically,” alanine would permit more hydrogen-bond formation, which might allow you to eliminate that choice.
That said, it seems almost impossible to rule out (without very technical knowledge or some provided experimental data) that the slightly larger alanine does not impair hydrogen bonding between collagen molecules via steric (spatial) interference. In simpler terms, since alanine is larger, you would think that it must somehow interfere with the hydrogen-bonding that occurs with the wild-type glycine.
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*Strictly speaking, it’s not the number of hydrogens but also the strength of the dipole that facilitates hydrogen bonding: a hydrogen bound to a strongly electronegative molecule like fluorine will “appear” more positive and, thus, hydrogen-bond more strongly with a nearby oxygen (compared with a hydrogen connected to carbon, for example).
Further reading:
From Molecular Biology of the Cell:
Hydroxylysines and hydroxyprolines are infrequently found in other animal proteins, although hydroxyproline is abundant in some proteins in the plant cell wall. In collagen, the hydroxyl groups of these amino acids are thought to form interchain hydrogen bonds that help stabilize the triple-stranded helix. Conditions that prevent proline hydroxylation, such as a deficiency of ascorbic acid (vitamin C), have serious consequences. (Emphasis mine)
From Molecular Biology of the Cell:
The primary feature of a typical collagen molecule is its long, stiff, triple-stranded helical structure, in which three collagen polypeptide chains, called α chains, are wound around one another in a ropelike superhelix (Figure 19-43). Collagens are extremely rich in proline and glycine, both of which are important in the formation of the triple-stranded helix. Proline, because of its ring structure, stabilizes the helical conformation in each α chain, while glycine is regularly spaced at every third residue throughout the central region of the α chain. Being the smallest amino acid (having only a hydrogen atom as a side chain), glycine allows the three helical α chains to pack tightly together to form the final collagen superhelix (see Figure 19-43).
the way I thought about it, is that the Osteogenesis Imperfecta results in defective osteoid production which is a secondary structure to collagen synthesis
Why would it be a disruption of the secondary structure of collagen molecules? I thought to form the tropocollagen triple helix hydrogen bonds are needed; and FA says failure of formation of the triple helix results in Osteogenesis Imperfecta.
submitted by wasabilateral(34), 2019-05-07T01:49:36Z
I think it has something to do with glycine (due to its small size it can fit in many places where other amino acids can not and hence it provides “structural compactness” to the collagen, i.e. put a kink in the alpha helix). If glycine is misplaced by something else, I don’t think pro-collagen can form its correct secondary structure.