PrionDB: Extraction of mutation data from the literature

2005, PrionDB.

This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes the selected point mutation and provides links to other documents. The sentence(s) where the point mutation P101L was found are listed after the table.

The mutated residues are also indicated in the family sequence alignments and hyperlinked to the corresponding mutation pages.

Point mutation P101L in PRIO_MOUSE

Point mutation:	P101L
Domain:	Not determined
General numbering (PrionDB):	-
Protein:	PRIO_MOUSE (Prnp,Prn-p)	Swiss-Prot Cross-reference table Family page
Other point mutations / same protein / same position	Point mutations at position 101 in PRIO_MOUSE
Other point mutations / same protein	List of mutations in PRIO_MOUSE
Family alignments	Mammalian prion proteins Prion proteins (PRP, PRNP)
Other point mutations / same position	Position 102 in Mammalian prion proteins family Position 102 in Prion proteins (PRP, PRNP) family
Reference:	Solid-state NMR studies of the secondary structure of a mutant prion protein fragment of 55 residues that induces neurodegeneration. Laws DD, Bitter HM, Liu K, Ball HL, Kaneko K, Wille H, Cohen FE, Prusiner SB, Pines A, Wemmer DE Proc Natl Acad Sci U S A 2001 Sep 25;98(20):11686-90.	Medline
Other point mutations / same article	List
Text source	HTML full text
Validation status	True positive

Relevant sentences:

P101L

Recent studies have shown that the fibrillar form of the P101L mutant of MoPrP(89-143) is capable of inducing prion disease in transgenic mice , whereas unaggregated or randomly aggregated samples do not provoke disease
Through analysis of 13C chemical shifts , we have determined that both wild-type and mutant sequence MoPrP(89-143) form a mixture of beta -sheet and alpha -helical conformations in the randomly aggregated state although the beta -sheet content in MoPrP(89-143 , P101L) is significantly higher than in the wild-type peptide
In a fibrillar state , MoPrP(89-143 , P101L) is completely converted into beta -sheet , suggesting that the formation of a specific beta -sheet structure may be required for the peptide to induce disease
Recently , Kaneko et al. (8 ) have worked with mice expressing low levels of PrP (MoPrP) carrying the P101L mutation , which causes Gerstmann-Straussler-Scheinker disease in humans , and causes disease in mice when expressed at high levels
They showed that a synthetic 55-aa fragment of MoPrP , residues 89-143 with the P101L mutation , can form beta -rich , fibrillar aggregates that stimulate disease when inoculated into these animals , whereas the peptide in nonfibrillar form does not (8 )
Thus , MoPrP (89-143 , P101L) presents an opportunity to gain insight into the structural features associated with the ability to cause disease and to learn about the mechanism of conversion from PrP C to PrP Sc
By placing 13C labels in six residues spread throughout the 55-residue peptide , the secondary structure was monitored in both the wild-type (wt) and P101L mutant forms of MoPrP(89-143)
Solid-state 13C NMR spectra of both the wt and P101L peptides exhibit a mixture of helical and extended conformation resonances , indicating substantial conformational heterogeneity and lability in the nonfibrillar state
After aggregation in an acetate-buffered acetonitrile / water solution , the solid-state 13C NMR spectrum of the P101L peptide loses all of the helical peaks , suggesting that the mutation affects not only the local secondary structure , but also the overall structure of the fragment
To convert the P101L and 3AV peptides to a fibrillar state , the samples were dissolved in a 50:50 (vol / vol) mixture of acetonitrile and acetate-buffered saline (100 mM NaCl , 20 mM NaOAc , pH 5.0)
A spectrum of the fibrillar MoPrP 89-143 P101L also was obtained with two-pulse phase-modulation decoupling (25 )
(B) Spectrum of MoPrP(89-143 , P101L) dried from water
(C) Spectrum of MoPrP(89-143 , P101L) peptide after conversion to fibrillar form by precipitation from acetonitrile / water
The higher ratio of beta -sheet to helical resonances in the unaggregated mutant MoPrP(89-143 , P101L) indicates the preference for this mutant to adopt beta -sheet structures
In Fig. 2 , the solid-state 13C NMR spectrum of wt MoPrP(89-143) is compared with the equivalent spectra of the mutant MoPrP(89-143 , P101L) peptide both before (Fig. 2 B) and after (Fig. 2 C) conversion to the aggregated , fibrillar state
This effect is most striking for the 13C alpha label in A114 , for which the ratio of helix to beta -sheet changes from approx 1:1 in the spectrum of the wt peptide to approx 1:2 in the spectrum of the P101L mutant
These results confirm that the PrP(89-143) fragment is structurally pliable and highly sensitive to mutations because a single amino acid substitution gives rise to conformational changes throughout the peptide , including amino acids over 30 residues away from the P101L substitution , as evidenced by the changes at A132
Comparison of measured chemical shifts in wt and mutant MoPrP(89-143) peptides Upon aggregation , the P101L mutant peptide appears to convert completely to an extended , beta -sheet-like form , as seen in Fig. 2 C
However , the resonances in the spectrum of the fibrillar P101L peptide (Fig. 2 C) appear broader than the randomly aggregated P101L peptide (Fig. 2 B)
In an attempt to better resolve these resonances , another spectrum of the aggregated P101L peptide also was obtained by using two-pulse phase-modulation (25 ) to improve 1H decoupling and narrow the 13C resonances
This finding is consistent with the observation of Kaneko et al. (8 ) that not all of the aggregated peptide is present in fibrillar form , and that a distribution of fibril lengths was present in the sample of the aggregated P101L peptide used for this study
In addition to the P101L mutant of MoPrP(89-143) , we examined the equivalent peptide from the SHaPrP sequence corresponding to residues 90-144
The mutant SHaPrP(89-143 , 3AV) peptide has been shown to aggregate when left in cold acetonitrile / acetate-buffered saline solution , as does MoPrP(89-143 , P101L) , although long fibrils were not seen with electron microscopy
The spectra of the mutant SHaPrP(89-143 , 3AV) peptide in the aggregated form show a further increase in the population of the extended conformers , very analogous to what was found for the MoPrP(89-143 , P101L) peptide
Because of the sequence differences , some of the 13C isotopic labels were different from those used for the P101L peptide
Although the mutant MoPrP(89-143 , P101L) also exhibits some degree of conformational heterogeneity , it is clear that the mutation drives the overall conformation of the peptide toward extended , beta -sheet-like conformations
The in vitro-prepared , fibrillar form of the MoPrP(89-143 , P101L) peptide stimulates disease in transgenic mice whereas other forms do not , indicating that the formation of a specific beta -sheet conformation may be necessary for the peptide to become 'infectious.' This behavior of the mutant peptide correlates with observations on PrP in transgenic mice and humans with Gerstmann-Straussler-Scheinker disease
The mutant SHaPrP(89-143 , 3AV) peptide formed aggregates rich in beta -sheet like the MoPrP(89-143 , P101L) peptide , whereas the wt SHaPrP(89-143) did not
Even if the stimulation of neurodegeneration by the mutant MoPrP(89-143 , P101L) peptide does not perfectly recapitulate all aspects of prion diseases , it seems to be a valuable model system for understanding features of the conformational change that PrP c undergoes as it is converted into PrP Sc

F.Horn (priondbcmbi.ru.nl), 22-Aug-2005