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 D177N 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 D177N in PRIO_MOUSE

Point mutation:	D177N
Cited point mutation:	D178N,Asp178Asn,Asp178
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 177 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 178 in Mammalian prion proteins family Position 178 in Prion proteins (PRP, PRNP) family
Reference:	Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. Liemann S, Glockshuber R Biochemistry 1999 Mar 16;38(11):3258-67.	Medline
Other point mutations / same article	List
Text source	HTML and PDF full texts
Validation status	True positive

Relevant sentences:

Asp178Asn

The figure was created with MOLMOL (93) ------------------------------------------------------------------------ We have introduced all these eight amino acid exchanges separately into mPrP(121-231) , as well as the Met129Val substitution that corresponds to the polymorphism in human PrP determining the disease phenotype linked to the Asp178Asn mutation (35) , and the replacement Thr190Val that corresponds to a polymorphism at positions 108 and 189 in mouse PrP determining the scrapie incubation time in mice (36)
Lane 1 , molecular mass standards ; 2 , wild-type mPrP(121-231) before induction with IPTG ; 3 , wild-type mPrP(121-231) 18 h after induction (same as for the variants shown in the following lanes) ; 4 , Met129Val ; 5 , Met129 / Asp178Asn ; 6 , Met129Val / Asp178Asn ; 7 , Val180Ile ; 8 , Thr183Ala ; 9 , Thr190Val ; 10 , Phe198Ser ; 11 , Glu200Lys ; 12 , Arg208His ; 13 , Val210Ile ; 14 , Gln217Arg
As examples , the spectra of the variants Asp178Asn / Met129Val (associated with FFI ; insoluble in the periplasm of E
In contrast , the variants Asp178Asn / Met129 , Asp178Asn / Met129Val , Thr183Ala , Phe198Ser , and Gln217LArg could not be obtained in a soluble form in the periplasm (Figure 3)
Thus , the lack of the soluble mPrP(121-231) variants Asp178Asn / Met129 , Asp178Asn / Met129Val , Thr183Ala , Phe198Ser , and Gln217LArg in the periplasm was due to protein aggregation and not due to proteolytic degradation of the polypeptide chains in vivo
The exchange of Asp178 by Asn destabilizes the variants Asp178Asn and Asp178Asn / Met129Val by a similar value (~7-8 kJ mol-1)
Thus , residue 129 has no influence on the destabilizing effect of the Asp178Asn exchange
hPrP(90-231) Asp178Asn aggregated in inclusion bodies as its murine counterpart , and the Pro102Leu substitution within the unstructured protein tail had no influence on protein stability
The five variants with the lowest stabilities , i.e. , Asp178Asn , Met129Val / Asp178Asn , Thr183Ala , Phe198Ser , and Glu217Arg , are exactly those which accumulated in periplasmic indusion bodies , while all other variants with wild type-like stabilities were obtained as soluble proteins (Figure 3 , Table 1)
The isosteric replacement of aspartate 178 to asparagine in the variants Asp178Asn and Asp178Asn / Met129Val affects a solvent-accessible salt bridge (Arg164-H (image) / O (image)-Asp178) and a hydrogen bond (Tyr128-H (image) / O (image)-Asp178) which connect both (image)-strands with helix 2 (27)
Although hydrogen bonds located at the molecular surface tend to contribute little to protein stability (0-2 kJ mol-1) (52 , 53) and the modified interactions of the asparagine side chain with the hydrogen bond partners are difficult to assess , the exchange Asp178Asn might further destabilize the proteins by a structural rearrangement between the (image)-sheet and helix 2
This polymorphism at the solvent-exposed residue 129 in the first (image)-strand of PrP C determines the disease phenotype linked to the Asp178Asn substitution in such a way that the Met129 / Asn178 allele segregates with FFI whereas the Val129 / Asn178 allele segregates with familial CJD (35)
The mPrP variants Pro102Leu , Asp178Asn / Met129 , Thr183Ala , and Glu200Lys (numbering according to human PrP) and a protein with an insertion of six additional octapeptide repeats displayed a number of biochemical hallmarks characteristic of PrP Sc such as detergent insolubility , protease resistance , aberrant membrane attachment , and hydrophobicity
In other studies , the expression of human PrP genes harboring the Asp178Asn mutation with Met129 / Val129 (82) and the Gln217Arg mutation (83) in human neuroblastoma cells has been described
These results suggested an instability of the proteins with the Asp178Asn exchange in vivo (82) and temperature-dependent protein misfolding in the case of the Gln217Arg variant (83)
We have introduced all these eight amino acid exchanges separately into mPrP(121-231) , as well as the Met129Val substitution that corresponds to the polymorphism in human PrP determining the disease phenotype linked to the Asp178Asn mutation (35) , and the replacement Thr190Val that corresponds to a polymorphism at positions 108 and 189 in mouse PrP determining the scrapie incubation time in mice (36)
The isosteric replacement of aspartate 178 to asparagine in the variants Asp178Asn and Asp178Asn / Met129Val affects a solvent-accessible salt bridge (Arg164H / O-Asp178) and a hydrogen bond (Tyr128-H / OAsp178) which connect both -strands with helix 2 (27)
Although hydrogen bonds located at the molecular surface tend to contribute little to protein stability (0-2 kJ mol-1) (52 , 53) and the modified interactions of the asparagine side chain with the hydrogen bond partners are difficult to assess , the exchange Asp178Asn might further destabilize the proteins by a structural rearrangement between the -sheet and helix 2
This polymorphism at the solvent-exposed residue 129 in the first -strand of PrPC determines the disease phenotype linked to the Asp178Asn substitution in such a way that the Met129 / Asn178 allele segregates with FFI whereas the Val129 / Asn178 allele segregates with familial CJD (35)

Asp178

The figure was created with MOLMOL (93) ------------------------------------------------------------------------ We have introduced all these eight amino acid exchanges separately into mPrP(121-231) , as well as the Met129Val substitution that corresponds to the polymorphism in human PrP determining the disease phenotype linked to the Asp178Asn mutation (35) , and the replacement Thr190Val that corresponds to a polymorphism at positions 108 and 189 in mouse PrP determining the scrapie incubation time in mice (36)
Lane 1 , molecular mass standards ; 2 , wild-type mPrP(121-231) before induction with IPTG ; 3 , wild-type mPrP(121-231) 18 h after induction (same as for the variants shown in the following lanes) ; 4 , Met129Val ; 5 , Met129 / Asp178Asn ; 6 , Met129Val / Asp178Asn ; 7 , Val180Ile ; 8 , Thr183Ala ; 9 , Thr190Val ; 10 , Phe198Ser ; 11 , Glu200Lys ; 12 , Arg208His ; 13 , Val210Ile ; 14 , Gln217Arg
As examples , the spectra of the variants Asp178Asn / Met129Val (associated with FFI ; insoluble in the periplasm of E
In contrast , the variants Asp178Asn / Met129 , Asp178Asn / Met129Val , Thr183Ala , Phe198Ser , and Gln217LArg could not be obtained in a soluble form in the periplasm (Figure 3)
Thus , the lack of the soluble mPrP(121-231) variants Asp178Asn / Met129 , Asp178Asn / Met129Val , Thr183Ala , Phe198Ser , and Gln217LArg in the periplasm was due to protein aggregation and not due to proteolytic degradation of the polypeptide chains in vivo
The exchange of Asp178 by Asn destabilizes the variants Asp178Asn and Asp178Asn / Met129Val by a similar value (~7-8 kJ mol-1)
Thus , residue 129 has no influence on the destabilizing effect of the Asp178Asn exchange
hPrP(90-231) Asp178Asn aggregated in inclusion bodies as its murine counterpart , and the Pro102Leu substitution within the unstructured protein tail had no influence on protein stability
The five variants with the lowest stabilities , i.e. , Asp178Asn , Met129Val / Asp178Asn , Thr183Ala , Phe198Ser , and Glu217Arg , are exactly those which accumulated in periplasmic indusion bodies , while all other variants with wild type-like stabilities were obtained as soluble proteins (Figure 3 , Table 1)
The isosteric replacement of aspartate 178 to asparagine in the variants Asp178Asn and Asp178Asn / Met129Val affects a solvent-accessible salt bridge (Arg164-H (image) / O (image)-Asp178) and a hydrogen bond (Tyr128-H (image) / O (image)-Asp178) which connect both (image)-strands with helix 2 (27)
Although hydrogen bonds located at the molecular surface tend to contribute little to protein stability (0-2 kJ mol-1) (52 , 53) and the modified interactions of the asparagine side chain with the hydrogen bond partners are difficult to assess , the exchange Asp178Asn might further destabilize the proteins by a structural rearrangement between the (image)-sheet and helix 2
This polymorphism at the solvent-exposed residue 129 in the first (image)-strand of PrP C determines the disease phenotype linked to the Asp178Asn substitution in such a way that the Met129 / Asn178 allele segregates with FFI whereas the Val129 / Asn178 allele segregates with familial CJD (35)
The mPrP variants Pro102Leu , Asp178Asn / Met129 , Thr183Ala , and Glu200Lys (numbering according to human PrP) and a protein with an insertion of six additional octapeptide repeats displayed a number of biochemical hallmarks characteristic of PrP Sc such as detergent insolubility , protease resistance , aberrant membrane attachment , and hydrophobicity
In other studies , the expression of human PrP genes harboring the Asp178Asn mutation with Met129 / Val129 (82) and the Gln217Arg mutation (83) in human neuroblastoma cells has been described
These results suggested an instability of the proteins with the Asp178Asn exchange in vivo (82) and temperature-dependent protein misfolding in the case of the Gln217Arg variant (83)
We have introduced all these eight amino acid exchanges separately into mPrP(121-231) , as well as the Met129Val substitution that corresponds to the polymorphism in human PrP determining the disease phenotype linked to the Asp178Asn mutation (35) , and the replacement Thr190Val that corresponds to a polymorphism at positions 108 and 189 in mouse PrP determining the scrapie incubation time in mice (36)
The isosteric replacement of aspartate 178 to asparagine in the variants Asp178Asn and Asp178Asn / Met129Val affects a solvent-accessible salt bridge (Arg164H / O-Asp178) and a hydrogen bond (Tyr128-H / OAsp178) which connect both -strands with helix 2 (27)
Although hydrogen bonds located at the molecular surface tend to contribute little to protein stability (0-2 kJ mol-1) (52 , 53) and the modified interactions of the asparagine side chain with the hydrogen bond partners are difficult to assess , the exchange Asp178Asn might further destabilize the proteins by a structural rearrangement between the -sheet and helix 2
This polymorphism at the solvent-exposed residue 129 in the first -strand of PrPC determines the disease phenotype linked to the Asp178Asn substitution in such a way that the Met129 / Asn178 allele segregates with FFI whereas the Val129 / Asn178 allele segregates with familial CJD (35)

D178N

------------------------------------------------------------------------ Table 1: Thermodynamic Stabilities of mPrP(121-231) Variants , mPrP(121-231) Wild Type , and Full-Length mPrP(23-231) Wild Type at pH 7.0 and 25 (image)C mPrP protein prion disease phenotype (image)G(image) fold (kJ mol-1)a (image)(image)G(image) fold (variant - wild type) b cooperativity (kJ mol-1 M-1)a [urea]1 / 2 (M) a mPrP(121-231) wt -29.7 ą 1.0 4.8 ą 0.2 6.2 mPrP(23-231) wt -25.5 ą 1.0 4.2 ą 1.9 4.1 ą 0.2 6.3 M129V polymorphism (human) -28.2 ą 1.0 1.4 ą 2.0 4.5 ą 0.2 6.3 D178N / M129 FFI -22.5 ą 0.7 7.2 ą 1.7 4.7 ą 0.1 4.8 D178N / V129 CJD -21.7 ą 0.9 8.0 ą 1.8 4.5 ą 0.2 4.9 V180I GSS -27.6 ą 0.8 2.1 ą 1.7 4.5 ą 0.1 6.2 T183A CJD -10.4 ą 2.1 19.3 ą 3.1 3.5 ą 0.5 3.0 T190V polymorphism (mouse) -30.3 ą 1.5 -0.7 ą 2.4 4.8 ą 0.2 6.4 F198S GSS -19.4 ą 0.8 10.3 ą 1.7 4.4 ą 0.2 4.5 E200K CJD -29.1 ą 1.5 0.6 ą 2.4 4.9 ą 0.3 5.9 R208H CJD -23.7 ą 1.5 6.0 ą 2.5 4.3 ą 0.3 5.6 V210I CJD -28.6 ą 1.6 1.1 ą 2.6 4.5 ą 0.3 6.3 Q217R GSS -20.8 ą 0.8 8.9 ą 1.7 4.5 ą 0.2 4.7 a The thermodynamic stabilities were measured by urea-induced equilibrium transitions (Figure 5)
Table 1: Thermodynamic Stabilities of mPrP(121-231) Variants , mPrP(121-231) Wild Type , and Full-Length mPrP(23-231) Wild Type at pH 7.0 and 25 °C mPrP protein prion disease phenotype G°fold (kJ mol-1)a G°fold (variant - wild type)b cooperativity (kJ mol-1 M-1)a [urea]1 / 2 (M)a mPrP(121-231) wt - -29.7 ( 1.0 - 4.8 ( 0.2 6.2 mPrP(23-231) wt - -25.5 ( 1.0 4.2 ( 1.9 4.1 ( 0.2 6.3 M129V polymorphism (human) -28.2 ( 1.0 1.4 ( 2.0 4.5 ( 0.2 6.3 D178N / M129 FFI -22.5 ( 0.7 7.2 ( 1.7 4.7 ( 0.1 4.8 D178N / V129 CJD -21.7 ( 0.9 8.0 ( 1.8 4.5 ( 0.2 4.9 V180I GSS -27.6 ( 0.8 2.1 ( 1.7 4.5 ( 0.1 6.2 T183A CJD -10.4 ( 2.1 19.3 ( 3.1 3.5 ( 0.5 3.0 T190V polymorphism (mouse) -30.3 ( 1.5 -0.7 ( 2.4 4.8 ( 0.2 6.4 F198S GSS -19.4 ( 0.8 10.3 ( 1.7 4.4 ( 0.2 4.5 E200K CJD -29.1 ( 1.5 0.6 ( 2.4 4.9 ( 0.3 5.9 R208H CJD -23.7 ( 1.5 6.0 ( 2.5 4.3 ( 0.3 5.6 V210I CJD -28.6 ( 1.6 1.1 ( 2.6 4.5 ( 0.3 6.3 Q217R GSS -20.8 ( 0.8 8.9 ( 1.7 4.5 ( 0.2 4.7 a The thermodynamic stabilities were measured by urea-induced equilibrium transitions (Figure 5)

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