Wednesday, April 17, 2019

Life (31) Chinese whispers

Back in 2008 Noha Mesbha published her excellent PhD thesis


which introduced the world, via this paper

The halophilic alkalithermophile Natranaerobius thermophilus adapts to multiple environmental extremes using a large repertoire of Na+(K+)/H+ antiporters

to Natranaerobius thermophilus and its antiporter nt-Nha. Which gives every impression of being a stand alone Na/H+ antiporter very closely related to the invariably operon controlled MrpA protein (named shaA) of Clostridium tetani. As she says

"Gene nt-Nha had 35% identity to the shaA (mrpA) gene of Clostridium tetani. The Mrp proteins belong to the monovalent cation/proton antiporter-3 protein family. ...Sequence analysis of the regions surrounding gene nt-Nha, however, did not show that it was part of an operon. This indicates that gene nt-Nha does not encode a subunit of an Mrp system, but rather a mono-subunit antiporter".

All well and good.

Then in 2010 Morino et al published

Single Site Mutations in the Hetero-oligomeric Mrp Antiporter from Alkaliphilic Bacillus pseudofirmus OF4 That Affect Na+/H+ Antiport Activity, Sodium Exclusion, Individual Mrp Protein Levels, or Mrp Complex Formation

Although the whole paper was about B subtilis (and how none of its Mrp subunits worked in any incomplete combination to antiport anything) they did make this throw-away comment:

"A MrpA/MrpD homologue encoded by a “stand alone” gene from polyextremophilic Natranaerobius thermophilus was recently reported to exhibit Na+/H+ and K+/H+antiport activity in anaerobically grown E. coli KNabc (24)"

where (24) is Mesbha's PhD paper. Notice that at this stage Mesbha's

nt-Nha ~ shaA, very closely related at 35% conserved gene sequence,

has been changed by Morino in to

nt-Nha ~ An "MrpA/MrpD homologue".

This is a just about acceptable per se because MrpA and MrpD are homologous to each other and nt-Nha is closely related to MrpA (shaA) of C tetani. But Mesbha herself never mentions MrpD in her 2009 paper or in her PhD thesis. And "MrpA/MrpD" is open to mis-interpretation. So we have "definition-creep" here, where nt-Nha could be accidentally seen as some sort of composite of MrpA in combination with MrpD. Ouch.

So next we have the 2017 offering by Jasso-Chávez et al

Functional Role of MrpA in the MrpABCDEFG Na+/H+ Antiporter Complex from the Archaeon Methanosarcina acetivorans

where we have this bizarre statement

"On the other hand, a fused MrpA-MrpD homolog in the alkaliphilic Natranaerobius thermophilus displayed Na+/H+ antiport activity when produced in E. coli strain KNabc (5, 28)"

Ref (5) is Morino's paper on B subtilis Mrp, in which one rather misleading citation suggests that nt-Nha is an "MrpA/MrpD homologue". This has developed to the extent that nt-Nha has now "become" a fusion of two genes to give a rather mythical monster.

Ref (28) is just Mesbha's PhD paper in which nothing of the sort was suggested.

So the Jasso-Chávez paper is utterly flawed due to misinterpreting a poorly phrased statement and adding an erroneous modification so as to grossly mis-represent an initial very solid finding by Mesbha. The Jasso-Chávez discussion of nt-Nha can be distilled as:

"Send three and fourpence, we're going to a dance".

The chance of their understanding how nt-Nha or their very own archaeal MrpA subunit work as a stand-alone antiporter appears to be approximately zero.

Very sad.


BTW The folks who worked from the actual gene to model the nt-Nha protein structure suggest that

"The final model presents 13 transmembrane α-helices organized in a similar arrangement as the NuoL subunit".

You know the picture but here it is again 'cos I think it's lovely

1 comment:

karl said...

This is a great example of a birth of an ungrounded narrative.

Sadly, medicine (outside of mechanical medicine (knee-jobs, sewing up cuts)) is riddled with such stuff..

To believe what one's MD says is a great leap of faith - and does a lot of harm.