Compositions and methods for dissolving protein aggregates
The present disclosure provides a polypeptide capable of dissolving protein aggregates. Also provided is a method of treating a neurodegeneration disease using the polypeptide.
1. A host cell comprising a polynucleotide encoding a polypeptide, wherein the polypeptide comprises a hydrophilic segment and a hydrophobic segment, wherein the hydrophilic segment comprises a sequence selected from the group consisting of:
(SEQ ID NO: 15)
TEPQEESEEEVEEPEER,
(SEQ ID NO: 16)
TDPQDDSDDDVDDPDDR,
(SEQ ID NO: 17)
TKPQKKSKKKVKKPKKR,
(SEQ ID NO: 18)
TRPQRRSRRRVRRPRRR,
(SEQ ID NO: 19)
ELDEESEDEVEEEQEDR,
(SEQ ID NO: 20)
KEEVDEDRDVDE,
and
(SEQ ID NO: 21)
EKSEQDLE,
or a sequence having at least 90% identity thereto,
wherein the hydrophobic segment comprises a sequence selected from the group consisting of:
(SEQ ID NO: 22)
TFYDQTVSNDL,
(SEQ ID NO: 23)
ANSAYYDAHPVTNGI,
(SEQ ID NO: 24)
PPQTAAREATSIPGFPAEGAIPLPV,
and
(SEQ ID NO: 25)
EGEVAEEPNSRP,
or a sequence having at least 90% identity thereto,
wherein the hydrophilic segment is at the N-terminus and the hydrophobic segment is at the C-terminus,
wherein the polypeptide has a length of 20-60 amino acid residues, and
wherein the polypeptide is capable of dissolving a protein aggregate.
2. The host cell of claim 1 , wherein the protein aggregate is fused in sarcoma (FUS) aggregate, TAR DNA-binding protein 43 (TDP43) aggregate, T-cell intracellular antigen-1 (TIA1) aggregate, chromosome 9 open reading frame 72 (C9orf72) aggregate or a combination thereof.
3. A host cell comprising a polynucleotide encoding a polypeptide, wherein the polypeptide comprises a hydrophilic segment and a hydrophobic segment, wherein the polypeptide comprises a sequence selected from the group consisting of:
(SEQ ID NO: 1)
TEPQEESEEEVEEPEERQQTPEVVPDDSGTFYDQTVSNDLE,
(SEQ ID NO: 2)
TDPQDDSDDDVDDPDDRQQTPDVVPDDSGTFYDQTVSNDLD,
(SEQ ID NO: 3)
TKPQKKSKKKVKKPKKRQQTPKVVPDDSGTFYDQTVSNDLK,
(SEQ ID NO: 4)
TRPQRRSRRRVRRPRRRQQTPRVVPDDSGTFYDQTVSNDLR,
(SEQ ID NO: 8)
ELDEESEDEVEEEQEDRQPSPEPVQENANSAYYDAHPVTNGIE,
(SEQ ID NO: 9)
KEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPG
FPAEGAIPLPV,
and
(SEQ ID NO: 10)
EGEVAEEPNSRPQEKSEQDLE,
or a sequence having at least 90% identity thereto, or a sequence having 1, 2, 3, 4, or 5 amino acid residue difference therefrom, and
wherein the polypeptide is capable of dissolving a protein aggregate.
4. The host cell of claim 3 , wherein the protein aggregate is fused in sarcoma (FUS) aggregate, TAR DNA-binding protein 43 (TDP43) aggregate, T-cell intracellular antigen-1 (TIA1) aggregate, chromosome 9 open reading frame 72 (C9orf72) aggregate or a combination thereof.