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Laboratory investigation; a journal of technical methods and pathology
03, 2018;98 (3): 272-282.

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

Richmond Muimo, Hani Mm Alothaid, Anil Mehta
Author Information
  1. Richmond Muimo: Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, UK.
  2. Hani Mm Alothaid: Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, UK.
  3. Anil Mehta: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
PMID: 29251738 DOI: 10.1038/labinvest.2017.121

Abstract

NM23 proteins NDPK-A and -B bind to the cystic fibrosis (CF) protein CFTR in different ways from kinases such as PKA, CK2 and AMPK or linkers to cell calcium such as calmodulin and annexins. NDPK-A (not -B) interacts with CFTR through reciprocal AMPK binding/control, whereas NDPK-B (not -A) binds directly to CFTR. NDPK-B can activate G proteins without ligand-receptor coupling, so perhaps NDPK-B's binding influences energy supply local to a nucleotide-binding site (NBD1) needed for CFTR to function. Curiously, CFTR (ABC-C7) is a member of the ATP-binding cassette (ABC) protein family that does not obey 'clan rules'; CFTR channels anions and is not a pump, regulates disparate processes, is itself regulated by multiple means and is so pleiotropic that it acts as a hub that orchestrates calcium signaling through its consorts such as calmodulin/annexins. Furthermore, its multiple partners make CFTR dance to different tunes in different cellular and subcellular locations as it recycles from the plasma membrane to endosomes. CFTR function in airway apical membranes is inhibited by smoking which has been dubbed 'acquired CF'. CFTR alone among family members possesses a trap for other proteins that it unfurls as a 'fish-net' and which bears consensus phosphorylation sites for many protein kinases, with PKA being the most canonical. Recently, the site of CFTR's commonest mutation has been proposed as a knock-in mutant that alters allosteric control of kinase CK2 by log orders of activity towards calmodulin and other substrates after CFTR fragmentation. This link from CK2 to calmodulin that binds the R region invokes molecular paths that control lumen formation, which is incomplete in the tracheas of some CF-affected babies. Thus, we are poised to understand the many roles of NDPK-A and -B in CFTR function and, especially lumen formation, which is defective in the gut and lungs of many CF babies.

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MeSH Term

AMP-Activated Protein Kinases
Animals
Calmodulin
Cystic Fibrosis Transmembrane Conductance Regulator
Humans
NM23 Nucleoside Diphosphate Kinases
Protein Domains
Protein Isoforms

Chemicals

CFTR protein, human
Calmodulin
NM23 Nucleoside Diphosphate Kinases
Protein Isoforms
Cystic Fibrosis Transmembrane Conductance Regulator
AMP-Activated Protein Kinases
NME1 protein, human
NME2 protein, human
Journal Article Review

Word Cloud

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