MCQsOnline - Online Collection of MCQs of Medical PG Entrance Exams.

MCQ stands for Multiple Choice Questions sometimes called as Objective type questions. Here we discuss the Old Question Papers, High Yield Points and Strategies with respect to the Indian Medical Post Graduate PG Entrance Exams like AIIMS,AIPG, JIPMER, CMC Vellore, PGI Chandigarh, UPSC, TNPSC, State PG Exams like Tamil Nadu PG (TN PG), Delhi PG, UPPG, Tamilnadu PG (TNPG), Karnataka PG, MAHE, COMED-K etc.

Target PG

PG Preparation

Related Portals

Search This Site

If you cannot locate what you want to find, please search using the box given below

Wednesday, January 09, 2008

More than 300 variants of human hemoglobin gene

045. There are more than 300 variants of human hemoglobin gene. Among these only a few are fatal. Hence, the most important factor to be conserved in a protein for its function is the:

1. Amino acid sequence

2. Ligand binding residues

3. Structure

4. Environment

Answer

2. Ligand binding residues

Reference:

Ä Harper 26th Edition Page 46 http://globin.cse.psu.edu/

Ä Genome Research 15:978-986, 2005 , Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity

Ä MBE Advance Access originally published online on June 27, 2003, Mol. Biol. Evol. 20(11):1754-1759. 2003

Lippincott 3rd Edition Page

Chaterjee 6th Edition Page

Quality

Thinker

Status
New

QTDF

Most books

Discussion

Missense mutations that impair protein function may result in disease. For diseases caused by such deleterious mutations, a simple but plausible model presents itself: The type of disease is dependent on when and where the protein's function is required in the organism. Given the type of disease, its severity is likely determined by at least three parameters: (1) the degree to which the function of the protein is impaired by the missense mutation; (2) variants of other genes that modulate the effect of the major locus, also referred to as genetic background; and (3) the environment.

Explanation

In the article 3rd cited, there is clear proof that ligand binding residues are conserved in a protein for its function. The key findings of the study are given here

Ä The significance of these findings was investigated further by observing the structural distribution of the 40 H positions identified in mammalian paralogous comparisons. These positions appeared evenly dispersed all over the structure, both at internal and external locations. Within the pool of H positions there were some likely to hold high functional significance, as they presented strong constraints in one subunit and much higher variability in the other. Consistently, the function of such residues was critical to only one chain. This was the case of six positions lying at inter-subunit contact surfaces.

o For example, leucine alpha 40 presented no substitutions over the whole mammalian tree, whereas its ß39 homolog was much more variable. This site is crucial in the alpha chain as it interacts with histidine ß146 at the sliding interface. Instead, we found no functional indication for residue ß39.

o Similarly, position ß60 displayed a remarkably conserved valine over the whole mammalian tree, whereas its alpha homolog switched to variable amino acids on different branches. A valine to glutamate mutation at this site is reported to lead to a highly unstable ß globin responsible for a severe form of thalassemia (Podda et al. 1991), whereas the alpha 55 homolog does not appear to be involved in any essential interaction.

Ä As an alternative, we focused on those residues showing highly constrained states in two sequence groups, but different in each group, and we named them CBD (for "constant but different"). As opposed to heterotachous positions, CBD sites were markedly overrepresented in paralogous ({alpha}/ß) comparisons, as opposed to orthologous ones ({alpha}/{alpha}, ß/ß), identifying them as likely signatures of functional specialization between the two subunits. When superimposed onto the three-dimensional structure of hemoglobin, CBD positions consistently appeared to cluster preferentially on inter-subunit surfaces, two contact areas crucial to function in vertebrate tetrameric hemoglobin.

Ä To confirm this prediction, we studied the distribution of CBD sites onto the hemoglobin quaternary structure. When superimposed onto the 3D structure of human adult hemoglobin, the 13 CBD sites identified in mammalian paralogous comparisons were concentrated at non-exposed locations. This concentration was confirmed by the fact that almost all of them (10/13) were indeed reported to occupy contact surfaces, such as central cavity, ligand binding pockets, and inter-subunit contacts. In particular, six CBD sites were directly involved in both {alpha}1ß2 (sliding) and {alpha}1ß1 (packing) interfaces (Perutz 1970; Shionyu, Takahashi, and Go 2001). For example, tyrosine {alpha}41 and its homolog arginine ß40 were identified as a highly constrained CBD couple in mammals. These sites interact with each other at the sliding surface in the oxy state. Another case is that of arginine {alpha}141 and its homolog histidine ß146, both of which presented no substitutions over the whole mammalian tree. These sites are involved in crucial interactions with different residues in the deoxy state. The high proportion of CBD positions at inter-subunit surfaces supports their role as potential indicators of functional divergence, because the refinement of interactions at these interfaces played a fundamental role in the evolution of critical functions such as modulation of oxygen affinity and cooperative binding (Perutz 1970).

Comments

I must confess that I do not find a satisfying evidence from a standard text book for this question, and hence have to go for the journal. But we have already had enough questions asked in AIPG and AIIMS that were not from textbooks, but from research papers just published or in some cases, papers that were not even published (but were researched in AIIMS). Once we had question on B Cell Acute Lymphoblastic Leukemia (ALL) with hypereosinophilia in AIIMS Nov 2004 and also in AIPG Jan 2005. More details are given in RxPG TargetPG Series AIPG 2005. Question 166

Tips

In aggregate, these studies suggest that mutations in evolutionarily conserved sites tend to impair protein function and lead to disease. There is also weak evidence that protein impairment and disease severity are somewhat correlated with the physicochemical difference between the original amino acid and the missense variant.

No comments:

Post a Comment