Tale

Comings and Goings

Tom Rapoport, Ph.D.

HHMI, Harvard Medical School

Published February 23, 2018

Cell biologist Tom Rapoport may be best known for studies of how proteins get in and out of a convoluted compartment inside cells called the endoplasmic reticulum (ER). But his personal backstory rivals his scientific achievements as a Howard Hughes Medical Institute Investigator at Harvard Medical School (HMS). His life has been intimately shaped by major political persecutions and social upheavals of 20th century Europe and America. Here’s the short version:

“My father was born in Russia into a Jewish family that emigrated during the Russian revolution to Vienna,” Rapoport wrote in a 2010 essay. “[In] the 1920s, [he] became a member of the Socialist party and later of the Communist party. He studied medicine and chemistry. While he was on a fellowship in Cincinnati, Ohio, the Nazis took over Austria and he could not return. In Cincinnati, he met my half-Jewish mother, who had emigrated from Nazi Germany and restarted her career as a pediatrician. I was born in Cincinnati, but 3 years later, in 1950, my parents became targets of the anticommunist campaign of Joseph McCarthy and returned to Europe, initially for a year in Austria. Because my dad was blacklisted, he could not find a job in Austria and we moved to East Germany, where he joined the faculty of Humboldt University in East Berlin. I was 4 years old when we arrived, and I stayed in Berlin until age 48.” In 1995, Tom and eight other members of his lab boarded a plane to Boston, where he has happily settled. He returns to hike in the Alps every year with at least one of his children.

Science begins at home

Rapoport credits his parents for his interest in science. He recalls stimulating discussions at the dinner table. His success in the Math Olympiads enabled him to go to a special high school for math and science. He developed a love for chemistry, thanks in part to Linus Pauling’s General Chemistry.

Rapoport attended Humboldt University on a special research program that combined undergraduate work with a PhD. East Germany’s PhD program also allowed two doctoral students to team up. Halfway through the seven-year program, he switched to biochemistry, putting him in an institute headed by his father. Rapoport ultimately earned two pairwise postgraduate degrees, but not before accidentally leaving a faucet on, flooding three floors of the institute, including his father’s office. His father made him renovate all of the damaged spaces.

The main publication in 1974 from his second doctorate remains his most-cited paper. The thesis, in partnership with Reinhart Heinrich, “described in quantitative terms the importance of an enzyme for the overall flux through a metabolic pathway and for the regulation of metabolite concentrations,” Rapoport recalls. The theory, now known as “metabolic control analysis (MCA),” was independently developed by another team at the same time and is lauded as an early contribution to the field of systems biology.

Moving to another institute in East Berlin, Rapoport became interested in protein translocation during a project to clone insulin mRNA. Fish, he learned, had larger Islets of Langerhans than mammals. On fish days, lab members lined up around a table to harvest the fresh carp parts they needed. (The rest of the fish was sold cheaply to grateful people lined up in front of the lab.) As part of that work, the group determined the first protein and gene sequences in East Germany.

Membrane ins and outs

Rapoport now wondered how a polypeptide’s zip-code like signal sequence is recognized by the membrane and how the polypeptide then moves through the membrane. With his students, Rapoport reported the first evidence that Sec61p forms the essential protein-conducting channel through the ER membrane for newly made proteins. Rapoport realized the similarities with the related bacterial SecY channel and proposed a unifying concept of protein translocation in 1994.

Science was difficult in East Germany, because of the isolation and lack of resources. When Rapoport made a rare trip to the United States, the FBI called each university host after he left to verify he was a “real scientist.” After the Berlin wall came down in 1989 and Germany was reunified in 1990, Rapoport suddenly found his grant applications funded in full. Yet, even the best and brightest East German scientists faced residual prejudices from their West German colleagues, who were now largely in charge at newly merged universities. Rapoport was denied a professorship at the new institution because of his past engagement in communist East Germany.

At Harvard, Rapoport continued to advance the field of protein translocation. In three main projects, his group has been working out how proteins cross into the ER membrane, how misfolded ER proteins are ejected back (“retrotranslocation”) into the cell cytosol for destruction (“ER-associated protein degradation, or ERAD”), and how the ER gets its shape. The ER is crucial for producing certain proteins and most of the lipids needed by other cell organelles. It occupies 10 percent of a cell’s volume and accounts for nearly half the membrane found in a typical animal cell.

While he insists much remains to be learned about ERAD in particular, Rapoport recently added a fourth project, the mechanism of protein import into peroxisomes, to attract students and postdoctoral fellows who want to make an impact on a less-studied biological problem. Peroxisomes are involved in energy metabolism and detoxification, and their malfunction results in serious human diseases.

In a nascent project, Rapoport also recently became interested in lung surfactants after glimpsing “amazing EM pictures” of the onion-like lipid bilayers in aveolar cells. Premature babies need surfactant spray, because their lung cells cannot yet generate surfactant.

“Every project has something to do with membranes,” Rapoport says. “My lab is known for using purified proteins and reconstituting a process with purified proteins. We start out with some murky cell biology problem – how proteins get across the membrane, how the shape of the membrane determines its function— and eventually understand it at molecular level.”

Shape of things to come

To learn these mechanistic details, the lab solves a lot of structures, often in collaboration with others. One highlight is the 2004 X-ray structure of an archaebacterial homolog of the Sec61p complex (with Stephen Harrison, a fellow Howard Hughes investigator at HMS). In a major result in 2016, they captured a structure of the active channel with a translocating polypeptide chain being pushed through.

This crystal structure of the active translocon adds important molecular insights about how proteins are inserted into the channel to be ferried through the bacterial cell membrane. Here, the translocating polypeptide (green) is being pushed through the hourglass-shaped SecY proteinconducting channel (brown and purple) by the SecA ATPase (blue). The analysis was published in *Nature* in March 2016. Courtesy T. Rapoport.

For proteins that do not fold correctly in the ER and retrotranslocate back to the cytosol, Rapoport’s group is working on a comprehensive picture of the ERAD pathway in yeast. In 2017, electron microscopy (EM) gave them a first glimpse of how the crucial Hrd1 channel allows proteins to cross the membrane. Ideally, they will catch Cdc48 ATPase, with its ring-like structure, pulling a misfolded protein back through the membrane.

The lab has EM collaborations with Tom Walz at Rockefeller University, Maofu Liao at HMS, and Christopher Akey at Boston University and has recently built independent EM capabilities as well. In June 2016, Rapoport decided he wanted to do more lab work, starting with crystallizing molecules too small for EM analysis. He found it a breeze: One-third of his trays grew crystals. His philosophy is to tackle the biological problem first, being flexible about learning whatever method is required to answer the question.

Rapoport, who turned 70 in 2017, anticipates a thriving lab for at least another decade or so. In this, too, there is family precedence. After all, his mother finally passed her PhD oral exam at age 102 in 2015, 77 years after her thesis on diphtheria was labeled with a yellow stripe, as Jews would soon be forced to wear yellow stars on their sleeves, and her oral exam canceled.

Looking ahead to where cell biology is heading, Rapoport advises young people to go into organ-specific cell biology, rather than trying to work on the fundamental processes of his generation. “Every cell type in a higher organism has a particular biology,” he says. “Major discoveries will be made and will be more medically relevant than in the past.”

-Carol Curzan Morton

Death Metal

Steven Damo

Published 28 April 2024

Context Matters

Bing Chen

Published 30 January 2024
The Crystal Whisperer

Sarah Bowman

Published 29 November 2023

Data in Motion

Nozomi Ando

Published 29 September 2023
The Monstrous Maw

André Hoelz

Published 28 June 2023

Second Takes

Andrea Thorn

Published 28 February 2023
Radical reactions

Yvain Nicolet

Published 31 January 2023

Floppy Physics

Eva Nogales

Published 30 November 2022
Structure of Equity

Jamaine Davis

Published 28 September 2022

Life and Death of a Cell

Evris Gavathiotis

Published 28 July 2022
Follow the glow

Kurt Krause

Published 29 April 2022

Resolution solutions

Willy Wriggers

Published 25 February 2022
Of enzymes and membranes

Ming Zhou

Published 28 October 2021

Step-by-step

Gabrielle Rudenko

Published 26 September 2021
Moving muscle

Montserrat Samso

Published 26 July 2021

Particle catcher

Stefan Raunser

Published 28 June 2021
Designer drugs

Ho Leung Ng

Published 25 February 2021

Right place, right time

Ernesto Fuentes

Published 29 January 2021
Shape-shifting secrets of membranes

James Hurley

Published 27 November 2020

Enzymatic action

Cynthia Wolberger

Published 28 September 2020
Rules of motion

Priyamvada Acharya

Published 31 July 2020

Cosmic Squared

Michael Cianfrocco

Published 27 June 2020
Kaps are Cool

Yuh Min Chook

Published 28 April 2020

Spiraling into focus

Carsten Sachse

Published 29 March 2020
Seeing cilia

Alan Brown

Published 27 February 2020

For the Love of EM

Guy Schoehn

Published 27 January 2020
Protein Puddles

Michael Rosen

Published 16 December 2019

Changing channels

Daniel Minor Jr.

Published 27 September 2019
Listening Tips

Marcos Sotomayor

Published 30 July 2019

Beyond Cool

Published 31 May 2019
Hao Wu

A Higher Order

Published 30 May 2019

Aye Aye Captain

Alexandre Bonvin

Published 29 April 2019
The PARP Family Family

John Pascal

Published 28 February 2019

Frame by frame

Nikolaus Grigorieff

Published 28 January 2019
Predicting Success

Bil Clemons

Published 18 December 2018

Curiouser and Curiouser

Ramaswamy Subramanian

Published 27 November 2018
Rely on This

Sjors Scheres

Published 26 October 2018

Proteins out of bounds

Gerhard Wagner

Published 27 September 2018
Hiding in plain sight

Gaya Amarasinghe

Published 27 July 2018

Jumping Genes

Orsolya Barabas

Published 27 June 2018
Data Whisperer

Karolin Luger

Published 30 May 2018

Flipping the Switch

Jacqueline Cherfils

Published 27 April 2018
Tooling Around

Andrew Kruse

Published 29 March 2018

Comings and Goings

Tom Rapoport, Ph.D.

Published 23 February 2018
Transcriptional Rhythm

Seth Darst

Published 27 January 2018

The Language of Gene Regulation

Daniel Panne

Published 21 November 2017
Not Your Average Protein

James Fraser

Published 23 October 2017

Message Received

Sebastien Granier

Published 24 August 2017
Resistance is Futile

Celia Schiffer

Published 28 July 2017

Twist of Fate

Leemor Joshua-Tor

Published 28 June 2017
Drug Designer

John Buolamwini

Published 30 May 2017

Mathematically Minded

James Holton

Published 28 April 2017
Garbage Out

Kay Diederichs

Published 30 March 2017

Fixer Upper

Brandt Eichman

Published 27 February 2017
Mobilizers

Phoebe Rice

Published 31 January 2017

Escape Artist

Katya Heldwein

Published 19 December 2016
Nature’s Confectioner

Jochen Zimmer

Published 29 November 2016

State of Fusion

Jason McLellan

Published 27 October 2016
Here Be Dragons

Brian Fox

Published 28 September 2016

SBGrid Assumes Ownership of PyMOLWiki

Published 15 September 2016
Pharm Team

Oleg Tsodikov

Published 24 August 2016

Spiro-Gyra

Alejandro Buschiazzo

Published 27 July 2016
Turning the DIALS

Nicholas Sauter

Published 29 June 2016

Pipeline Dreams

Bridget Carragher and Clint Potter

Published 26 April 2016
U-Store-It

The SBGrid Data Bank provides an affordable and sustainable way to preserve and share structural biology data

Published 28 March 2016

Big Questions, Big Answers

Jennifer Doudna

Published 22 February 2016
Not a Structural Biologist

Enrico Di Cera

Published 17 December 2015

Divide and Conquer

Kevin Corbett

Published 19 November 2015
Computing Cellular Clockworks

Klaus Schulten

Published 23 October 2015

Trans-Plant

Gang Dong

Published 26 September 2015
Keep on Moving

James Berger

Published 23 August 2015

Totally Tubular

Antonina Roll-Mecak

Published 27 July 2015
From Disorder, Function

Julie Forman-Kay

Published 29 June 2015

Into Alignment

Geoff Barton

Published 27 May 2015
Two Labs, Many Methods

Michael Sattler

Published 28 April 2015

Picture This

Georgios Skiniotis

Published 20 March 2015
Intron Intrigue

Navtej Toor

Published 20 February 2015

Cut and Paste

Martin Jinek

Published 28 January 2015
Basics and Beyond

Qing Fan

Published 18 December 2014

Bloodletting and Other Studies

Pedro José Barbosa Pereira

Published 25 November 2014
Wire Models, Wired

A brief history of UCSF Chimera

Published 29 October 2014

In Search of…New Drugs

Doug Daniels

Published 30 September 2014
Ilyas Hamdi

Published 30 September 2014

An Affinity for Affinity…and Corals

John C. Williams

Published 29 August 2014
Pete Meyer, Ph.D.

Research Computing Specialist

Published 22 August 2014

Justin O'Connor

Sr. System Administrator

Published 20 August 2014
Carol Herre

Software Release Engineer

Published 15 August 2014

Elizabeth Dougherty

Science Writer

Published 13 August 2014
Andrew Morin, Ph.D.

Policy Research Fellow

Published 11 August 2014

Jason Key, Ph.D.

Associate Director of Technology and Innovation

Published 8 August 2014
Piotr Sliz, Ph.D.

Principal Investigator, SBGrid

Published 1 August 2014

New Kid on the Block

James Chen

Published 29 July 2014
Membrane Master

Tamir Gonen

Published 30 June 2014

The Natural Bridge

Piotr Sliz

Published 13 June 2014
Surprise, Surprise

Catherine Drennan

Published 26 April 2014

Gone Viral

Olve Peersen

Published 20 March 2014
All Who Wander Are Not Lost

Frank Delaglio

Published 24 February 2014

The Raw and the Cooked

Graeme Winter

Published 24 January 2014
Vacc-elerator

Peter Kwong

Published 17 December 2013

Structural Storyteller

Karin Reinisch

Published 15 November 2013
The Fixer

Jane Richardson

Published 28 October 2013

Inside the Box

Mishtu Dey

Published 17 September 2013
Sensing a Change

Brian Crane

Published 16 August 2013

Towards Personalized Oncology

Mark Lemmon

Published 16 July 2013
Brush with Fame

Yizhi Jane Tao

Published 14 June 2013

Toxic Avenger

Borden Lacy

Published 21 May 2013
Pushing the Boundaries

Stephen Harrison

Published 22 April 2013

Strength in Numbers

Joseph Ho

Published 18 March 2013
One Lab, Many Methods

Wesley Sundquist

Published 12 February 2013

Unplanned Pioneer

Tim Stevens

Published 15 January 2013
From Actin to Action

Emil Pai

Published 11 January 2013

Unstructured

A Brief History of CCP4

Published 12 December 2012
Stop, Collaborate and Listen

Eleanor Dodson

Published 5 November 2012

X-PLORer

Axel Brunger

Published 1 October 2012
Share the Wealth

Zbyszek Otwinowski

Published 22 August 2012

Unraveling RNA

Anna Pyle

Published 18 July 2012
Sharper Image

Pawel Penczek and SPARX

Published 4 June 2012

Creative Copy Cat

Pamela Bjorkman

Published 25 April 2012
Charm and Diplomacy

Gerard Kleywegt

Published 7 March 2012

From Curiosity to Cure

Marc Kvansakul

Published 13 December 2011
The Lure of the Sandbox

Paul Emsley and Coot

Published 15 October 2011

Springsteen, Tolkien, Protein

Alwyn Jones and Frodo

Published 17 June 2011
Structures Solved Simply

Paul Adams and Tom Terwilliger on Phenix

Published 2 June 2011

Escape from the Darkroom

Wolfgang Kabsch and XDS

Published 19 May 2011
Playing the Odds

Randy Read and Phaser

Published 19 May 2011

Crystallography for Kids

Lynne Howell

Published 17 May 2011
Better, Faster, Stronger, More

Victor Lamzin and ARP/wARP

Published 17 May 2011

Side-Track to Success

Ning Zheng

Published 13 May 2011

Science begins at home

Membrane ins and outs

Shape of things to come

Death Metal

Context Matters

The Crystal Whisperer

Data in Motion

The Monstrous Maw

Second Takes

Radical reactions

Floppy Physics

Structure of Equity

Life and Death of a Cell

Follow the glow

Resolution solutions

Of enzymes and membranes

Step-by-step

Moving muscle

Particle catcher

Designer drugs

Right place, right time

Shape-shifting secrets of membranes

Enzymatic action

Rules of motion

Cosmic Squared

Kaps are Cool

Spiraling into focus

Seeing cilia

For the Love of EM

Protein Puddles

Changing channels

Listening Tips

Beyond Cool

Hao Wu

Aye Aye Captain

The PARP Family Family

Frame by frame

Predicting Success

Curiouser and Curiouser

Rely on This

Proteins out of bounds

Hiding in plain sight

Jumping Genes

Data Whisperer

Flipping the Switch

Tooling Around

Comings and Goings

Transcriptional Rhythm

The Language of Gene Regulation

Not Your Average Protein

Message Received

Resistance is Futile

Twist of Fate

Drug Designer

Mathematically Minded

Garbage Out

Fixer Upper

Mobilizers

Escape Artist

Nature’s Confectioner

State of Fusion

Here Be Dragons

SBGrid Assumes Ownership of PyMOLWiki

Pharm Team

Spiro-Gyra

Turning the DIALS

Pipeline Dreams

U-Store-It

Big Questions, Big Answers

Not a Structural Biologist

Divide and Conquer

Computing Cellular Clockworks

Trans-Plant

Keep on Moving

Totally Tubular

From Disorder, Function

Into Alignment

Two Labs, Many Methods

Picture This

Intron Intrigue