Polyalanine-independent Conformational Conversion of Nuclear Poly(A)-binding Protein 1 (PABPN1)

Winter, Reno; Kühn, U.; Hause, Gerd; Schwarz, Elisabeth

doi:10.1074/jbc.m112.362327

Cited by 13 publications

(18 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Purified fragments of the N-terminal domain of PABPN1 carrying an expanded stretch of 17 alanines show a greater propensity to form fibrils that are more resistant to solubilization than fragments with 10 alanines [59]. However, subsequent work using full-length PAB-PN1 revealed that fibril formation is independent of the alanine tract and that the C-terminal domain confers aggregation [60] as both the wild-type and alanine-expanded PABPN1 proteins could form aggregates and removing the N-terminal stretch of alanines did not prevent aggregation [60]. Thus, these in vitro studies do not support a model where alanineexpanded PABPN1 is more prone to aggregation, at least in vitro, than the wild-type protein.…”

Section: Approaches Used To Study the Effects Of Mutant Pabpn1mentioning

confidence: 99%

PABPN1: molecular function and muscle disease

et al. 2013

View full text Add to dashboard Cite

The polyadenosine RNA binding protein, polyadenylate-binding nuclear protein 1 (PABPN1), plays key roles in post-transcriptional processing of RNA. Although PABPN1 is ubiquitously expressed and presumably contributes to control of gene expression in all tissues, mutation of the PABPN1 gene causes the disease Oculopharyngeal Muscular Dystrophy (OPMD), in which a limited set of skeletal muscles are effected. A major goal in the field of OPMD research is to understand why mutation of a ubiquitously expressed gene leads to a muscle-specific disease. PABPN1 plays a well-documented role in controlling the poly(A) tail length of RNA transcripts but new functions are emerging through studies that exploit a variety of unbiased screens as well as model organisms. This review addresses: (1) the molecular function of PABPN1 incorporating recent findings that reveal novel cellular functions for PABPN1 and (2) the approaches that are being used to understand the molecular defects that stem from expression of mutant PABPN1. The long-term goal in this field of research is to understand the key molecular functions of PABPN1 in muscle as well as the mechanisms that underlie the pathological consequences of mutant PABPN1. Armed with this information, researchers can seek to develop therapeutic approaches to enhance the quality of life for patients afflicted with OPMD.

show abstract

Section: Approaches Used To Study the Effects Of Mutant Pabpn1mentioning

confidence: 99%

PABPN1: molecular function and muscle disease

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Interactions of the poly-Ala stretch with functional domain of the protein may also trigger pathological behavior of PABPN1. But before concluding this type of remarks, further conformational study with the whole N-terminal domain and protein PABPN1 in native as well as mutant form should be considered as Winter et al report poly-Ala independent aggregation of PABPN1 protein [35]. The helix adopting character of poly-Ala stretch and its relation to pathological mechanism by mutant PABPN1 will be published in our forthcoming publication.…”

Section: Discussionmentioning

confidence: 93%

Gly→Ala Point Mutation and Conformation of Poly-Ala Stretch of PABPN1: A Molecular Dynamics Study

Shafique¹,

Garg²,

Nandel³

2015

JBPC

View full text Add to dashboard Cite

Single nucleotide replacing mutations in genes cause a number of diseases, but sometimes these mutations mimic other genetic mutations such as trinucleotide repeats expansions. A mutation in codon GGG→GCG results in Gly→Ala at the N-terminal of PABPN1 protein that mimics the trinucleotide repeat expansion disease called Oculopharyngeal muscular dystrophy (OPMD). Molecular dynamics simulations in water with peptide models having sequence Ac-A10-GA2GG-NHme (peptide A) and Ac-A10A3GG-NHme (peptide B) reveal an increase in the length of helical segment in peptide B. The α-helical length is found to be stable in peptide B with starting geometry of a right handed helix, while in the case peptide A, the helical length is short. The interactions of water molecules at terminals, side chain-backbone interactions and hydrogen bonds provide stability to resultant conformation. The adopted helix by the poly-Ala stretch may lead to masking some other active parts of the PABPN1 that may trigger the aggregation, decrease in degradation and/or impaired function of protein. Hence, further studies with N-terminal may be helpful to understand unclear disease mechanism.

show abstract

“…Solid-state NMR studies identified a rigid fibrillar core that contained the alanine segment (Sackewitz et al, 2008a). Unexpectedly, fibril formation of the fulllength protein was not alanine-dependent (Winter et al, 2012). Furthermore, fibrils formed by full-length PABPN1 did not exhibit the high resistance against solubilizing agents as those of the N-terminal domain, and it became evident that fibrils from the N-terminal domain and fulllength PABPN1 do not share any common features.…”

Section: The Link Between Alanine Extensions and Protein Function Or mentioning

confidence: 97%

“…It is so far unclear why fibril formation alaninedependent in the case of the N-terminal domain but not in the context of full-length PABPN1 (Winter et al, 2012). Alanine peptides have been called conformational chameleons because they display the whole spectrum, from high to low α-helicities, depending on the flanking residues (Miller et al, 2001).…”

Section: The Link Between Alanine Extensions and Protein Function Or mentioning

confidence: 99%

Influence of the polypeptide environment next to amyloidogenic peptides on fibril formation

Damm

Schwarz

2014

Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Alternative folding or fibril formation of proteins is associated with many diseases. Although uncertainty remains for many diseases as to whether the fibrils themselves constitute the main pathogenicity factor, the biophysics or molecular steps leading to fibrils cannot easily be reduced to a common denominator. To date, it is known that fibrils can form (i) upon aberrant (over-)production or false processing, (ii) upon infection with prions that act as seeds and induce unfolding of a thus far native protein--as has been shockingly experienced during the bovine spongiform encephalopathy episode, (iii) when mutations are present that increase the propensity of an otherwise stable protein to aggregate, or (iv) when mutation decreases the overall stability of an individual protein. This review intends to highlight some of the biochemical and biophysical mechanisms that favor fibril formation. Special emphasis is given on the relevance of the polypeptide environment of amyloidogenic segments and the currently discussed driving forces of fibril formation.

show abstract

Polyalanine-independent Conformational Conversion of Nuclear Poly(A)-binding Protein 1 (PABPN1)

Cited by 13 publications

References 44 publications

PABPN1: molecular function and muscle disease

PABPN1: molecular function and muscle disease

Gly→Ala Point Mutation and Conformation of Poly-Ala Stretch of PABPN1: A Molecular Dynamics Study

Influence of the polypeptide environment next to amyloidogenic peptides on fibril formation

Contact Info

Product

Resources

About