Exhibit 5.1

March 23, 2018

Proteostasis Therapeutics, Inc.

200 Technology Square, 4^th Floor

Cambridge, Massachusetts 02139

Ladies and Gentlemen:

We have acted as counsel to you in connection with your filing of a Registration Statement on Form S-3 (as amended or supplemented, the “Registration Statement”) filed on June 7, 2017 with the Securities and Exchange Commission (the “Commission”) pursuant to the Securities Act of 1933, as amended (the “Securities Act”), relating to the registration of the offering by Proteostasis Therapeutics, Inc., a Delaware corporation (the “Company”) of up to $125,000,000 of any combination of securities of the types specified therein. We are delivering this opinion letter in connection with the prospectus (the “Prospectus”) contained in the Registration Statement which relates to the offering by the Company of up to $50,000,000 in shares (the “Shares”) of the Company’s common stock, par value $0.001 per share (“Common Stock”) covered by the Registration Statement. The Shares are being offered and sold by the Company through the sales agent named in, and pursuant to, the Sales Agreement, dated March 23, 2018, between the Company and the sales agent.

We have reviewed such documents and made such examination of law as we have deemed appropriate to give the opinions set forth below. We have relied, without independent verification, on certificates of public officials and, as to matters of fact material to the opinions set forth below, on certificates of officers of the Company.

For purposes of the opinion set forth below, we have assumed that no future issuance or issuances of securities of the Company will cause the number of Shares to be issuable under the Sales Agreement to exceed the total number of authorized shares of Common Stock under the Company’s certificate of incorporation, as amended and then in effect.

For purposes of the opinions set forth below, we refer to the following as “Future Approval and Issuance”: (a) the approval by the Company’s board of directors (or a duly authorized committee of the board of directors) of the issuance of the Shares (the “Approval”) and (b) the issuance of the Shares in accordance with the Approval and the receipt by the Company of the consideration (which shall not be less than the par value of such Shares) to be paid in accordance with the Approval.

The opinion set forth below is limited to the Delaware General Corporation Law.

Proteostasis Therapeutics, Inc.

March 23, 2018

Page 2

Based on the foregoing, we are of the opinion that the Shares have been duly authorized and, upon Future Approval and Issuance, will be validly issued, fully paid and nonassessable.

We hereby consent to the inclusion of this opinion as Exhibit 5.1 to the Registration Statement. In giving our consent, we do not admit that we are in the category of persons whose consent is required under Section 7 of the Securities Act or the rules and regulations thereunder.

Very truly yours,

/s/ GOODWIN PROCTER LLP

GOODWIN PROCTER LLP